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Endocrine Reviews 21(5): 457– 487
Copyright © 2000 by The Endocrine Society
Printed in U.S.A.

Neuroendocrinology of the Skin*


ANDRZEJ SLOMINSKI AND JACOBO WORTSMAN
Department of Pathology (A.S.), University of Tennessee, Memphis, Tennessee 38163; and Department
of Medicine (J.W.), Southern Illinois University, Springfield, Illinois

ABSTRACT derlie a role for these agents in the skin response to stress. The
The classical observations of the skin as a target for melanotropins endocrine mediators with their receptors are organized into dermal
have been complemented by the discovery of their actual production and epidermal units that allow precise control of their activity in a
at the local level. In fact, all of the elements controlling the activity field-restricted manner. The skin neuroendocrine system communi-
of the hypothalamus-pituitary-adrenal axis are expressed in the skin cates with itself and with the systemic level through humoral and
including CRH, urocortin, and POMC, with its products ACTH, neural pathways to induce vascular, immune, or pigmentary changes,
␣-MSH, and ␤-endorphin. Demonstration of the corresponding recep- to directly buffer noxious agents or neutralize the elicited local re-
tors in the same cells suggests para- or autocrine mechanisms of actions. Therefore, we suggest that the skin neuroendocrine system
action. These findings, together with the demonstration of cutaneous acts by preserving and maintaining the skin structural and functional
production of numerous other hormones including vitamin D3, PTH- integrity and, by inference, systemic homeostasis. (Endocrine Re-
related protein (PTHrP), catecholamines, and acetylcholine that views 21: 457– 487, 2000)
share regulation by environmental stressors such as UV light, un-

I. Introduction B. Hypothalamic and pituitary hormones


II. Structure of the Skin C. Neuropeptides and neurotrophins
A. Developmental biology D. Neurotransmitters/neurohormones
B. Anatomy and histology E. Thyroid hormones
C. Physiology F. Sex steroid hormones
III. Skin as a Target for Neuroendocrine Signals G. Other steroid hormones
A. CRH and urocortin receptors (CRH-R) V. Molecular and Structural Basis for the Organizational
B. Melanocortin receptors (MC-R) Integration of Neuroendocrine Elements of the Skin
C. Opioid receptors VI. Regulation of Cutaneous Neuroendocrine System
D. GH receptor (GH-R) A. Solar radiation
E. PRL and LH/CG receptors (LH/CG-R) B. Hair cycle
F. Neurokinin receptors (NK-R) C. Cytokines
G. Calcitonin gene-related peptide receptor (CGRP-R) D. Degradation or inactivation of hormones and neu-
H. Vasoactive intestinal peptide receptor (VIP-R) rotransmitters
I. Neutrophin (NT) receptors VII. Regulation of Cutaneous Vitamin D Production
J. Miscellaneous neuropeptide receptors A. Vitamin D3 production
K. PTH and PTH-related protein (PTHrP) receptors B. Precutaneous regulation
L. Vitamin D receptor (VDR) C. Cutaneous regulation
M. Glucocorticoid and mineralocorticoid receptors D. Postcutaneous regulation
N. Androgen and estrogen receptors E. General comments
O. Thyroid hormone receptors VIII. Final Comments and Future Directions
P. Cholinergic receptors
Q. Adrenergic receptors
R. Glutamate receptors I. Introduction
S. Serotonin receptors
T. Histamine receptors
U. Miscellaneous receptors
T he skin is the largest body organ and functions as a
metabolically active biological barrier separating in-
ternal homeostasis from the external environment. Depend-
IV. Skin as a Source of Hormones and Neurotransmitters ing on anatomic localization and environmental influences,
A. PTHrP the skin shows remarkable functional and structural diver-
sity (1– 4), since it is continuously exposed to fluctuating
Address reprint requests to: Andrzej Slominski, M.D., Ph.D., Depart- external information represented by solar and thermal radi-
ment of Pathology, RM576-BMH Main, University of Tennessee, 899 Mad- ation, mechanical energy, changes in humidity, and/or
ison Avenue, Memphis, Tennessee 38163. E-mail: aslominski@utmem.edu chemical and biological insults. The maintenance of skin
* This work was supported by grants from National Science Foun-
dation (NSF) (IBN-9604364, IBN-9896030, and IBN-9405242), and Amer- structural integrity is therefore critical and must be served by
ican Cancer Society, Illinois Division (no. 99 –51) to A.S., and internal rapid mechanisms to restore the barrier properties of the
funding from the Department of Pathology, University of Tennessee. epidermis when disrupted by external trauma. Maintenance

457

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458 SLOMINSKI AND WORTSMAN Vol. 21, No. 5

of organ, and hence systemic homeostasis, requires a special sensory nerves, or skin-activated circulating cells, or through
cutaneous property, the capability to recognize and integrate direct release into the circulation as neurohormones or medi-
appropriate signals with a high degree of specificity. Such ators. This review will end by setting the stage for future basic
sensory mechanism must be widely distributed, efficiently and clinical research.
self-regulated in intensity and field of activity, and endowed
with the capability of differentiating environmental noise
from biologically relevant signals (5, 6). To some extent, these II. Structure of the Skin
mechanisms are represented by the skin immune system,
A. Developmental biology
activated by biological insults or trauma (7); and in humans,
by the pigmentary system, activated or modified by solar The epithelial skin structures, e.g., epidermis, hair follicle,
radiation (8 –10). However, as presented in this work, the and sebaceous, apocrine, and eccrine glands, all derive from
main component in this critical skin function is the level of the embryonal outer epithelium, which originates from ec-
activity of the local neuroendocrine system. toderm (29). Nonkeratinocytic cells of the epidermis and hair
Over the last decade, it has become increasingly apparent follicle that include melanocytes and Merkel cells are also of
that the skin, particularly the epidermis, has powerful meta- ectodermal origin, but melanocytes migrate to the epidermis
bolic and endocrine capabilities (11, 12). For example, the skin from the neural crest (1, 3, 4, 29). Cell populations of meso-
synthesizes vitamin D, which enters the circulation and, upon dermal origin comprise the Langerhans cells and the T lym-
activation, exerts profound metabolic and endocrine effects (13, phocytes, which include the T␥␦ type expressed in mouse
14). Resident skin cells also synthesize and release the hormones epidermis and hair follicle and the sparse, mostly T␣␤ cells
parathyroid hormone-related protein (PTHrP) (15), POMC-de- expressed in human epidermis (7). All of the dermal com-
rived MSH, ACTH, and ␤-endorphin peptides (5, 16, 17), the ponents are of mesodermal origin, with the exception of
CRH and urocortin peptides (18, 19), the neurotransmitters nerves and specialized sensory receptors that develop from
catecholamines and acetylcholine (20, 21), and precursors to the ectoderm (1, 3, 4, 7, 29). The dermal cellular populations
biogenic amines (9, 21–23). While production of some of these include fibroblasts/fibrocytes/myofibroblasts, adipocytes,
factors is not constitutive, it does respond to specific inductive monocytes/macrophages, mast cells, Langerhans cells, T
stimuli. The skin is also a site for activation of steroid hormones lymphocytes, dendrocytes, smooth muscle cells, and vascu-
such as the conversion of testosterone to 5␣-dihydrotestoster- lar and lymphatic endothelial cells. Fibrocytes arise by dif-
one or to estradiol, or the conversion of T4 to T3 (4, 11, 12). These ferentiation of stellate mesenchymal cells present in the pri-
locally generated hormones and neurotransmitters can act in a mordial dermis, whereas adipocytes differentiate from
paracrine or autocrine fashion. Moreover, the presence of nu- subdermal mesenchymal cells that surround newly formed
merous nerve endings and a rich vascular network provide blood vessels. Macrophages, mast cells, Langerhans cells,
additional mechanisms for the expression of neuroendocrine and dendrocytes migrate to the skin from the bone marrow.
functions, e.g., transmission of regulatory signals to the global Formation of the adnexal structures results from precise
or central systems via the vascular system, or through the af- mesenchymal epithelial interactions producing down
ferent neural network. growth of primordial adnexal structures to reach the reticular
This emerging concept, of skin as a neuroendocrine organ, dermis and subcutis (1, 3, 4, 29 –31). The multidirectional
is a relatively new addition to the field of cutaneous biology; interaction between cells of ectodermal and mesodermal or-
it combines concepts from immunology, endocrinology, and igin results in a cohesive unified skin structure that, never-
neurobiology to unravel the multidirectional communica- theless, maintains a degree of heterogeneity expressed by
tions between brain, the endocrine and immune systems, and marked regional differences (1, 4, 29).
peripheral organs (24 –28). In this regard, the skin has a In the context of this review it must be noted that brain,
unique role because of its location, size, and relative func- peripheral nervous system, retina, and medulla of adrenal
tional diversity. Moreover, cutaneous signals sent to neu- gland are also of ectodermal origin, whereas olfactory epi-
roendocrine centers may play modulatory roles, although thelium and olfactory nerves, anterior lobe of hypophysis,
peripheral intraorgan or intersystemic communications are and epithelial elements of the mammary gland all derive
also necessary to maintain global and local homeostasis. from the outer epithelium (29). Mesodermal structures in-
We will presently review evidence on the production of clude the immune system, endothelium of blood vessels,
hormones and neurotransmitters by the skin and on the ex- adrenal cortex, and gonadal epithelium and stroma (7, 29).
pression of the corresponding receptors. Cutaneous regulation These embryologic associations may determine the potential
of neuroendocrine communication will be analyzed and its capability for resident skin cells to produce molecules similar
function discussed within the context of organ homeostasis. to their close or distant relatives. Thus, cellular lineage may
Data on the experimental characterization of receptors for neu- predict neuroendocrine functional activity.
rohormones in skin cells will be reviewed, including regulation
of expression, ligand production, and characterization of signal B. Anatomy and histology
transduction pathways. Pertinent data will be included with the
understanding that the mere presence of a substance in a culture The skin is composed of two main compartments: the
system of skin cells does not necessarily imply that the sub- epidermis with the adnexal epithelial structures and the der-
stance has physiological relevance in vivo. Special attention will mis with the nonepithelial elements of adnexa (1– 4). While
be given to intraorgan communication and to the potential not a skin component, the subcutaneous fat is closely related
systemic or central effects of skin-produced factors acting on to the skin anatomically and functionally. Structure and

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October, 2000 NEUROENDOCRINOLOGY OF THE SKIN 459

thickness of both epidermis and dermis vary according to networks do show regional differences according to ana-
anatomic location; thus, the average thickness of the epider- tomic sites and also have topographical specificity by dis-
mis is 0.1 mm, but in the acral areas is up to 1.6 mm thick. tributing into well defined areas called dermatomes. The
The latter regions contain thick cornified and granular layers torso, extremities, posterior scalp, and neck are supplied by
and numerous eccrine units and nerve endings but lack sensory nerves arising from dorsal root ganglia of the spinal
folliculosebaceous-apocrine units. In contrast, facial skin cord, whereas face, most of the scalp, and upper anterior neck
contains numerous vellus follicles with prominent sebaceous are innervated by trigeminal nerve branches.
glands; skin in the axilla and groins is characterized by nu-
merous apocrine glands, back skin has very thick reticular C. Physiology (1–22, 30 –35)
dermis, and scalp skin contains large terminal hair follicles
routed deep into the subcutaneous fat. In furry animals, The most important function of the skin, determined by its
terminal hair follicles cover most of the body, serving as location at the interface between external and internal environ-
insulating cover and as touch organs (30 –32). ments, is that of physical barrier. This is established in the
The basal membrane zone separates the epidermis and epidermis by a precisely regulated gradient of keratinocyte
epithelial adnexal structures from the dermis. Beneath the differentiation stages, which forms a highly impermeable pro-
basement membrane is a thin zone of adventitial dermis tein-lipid layer at the outer-most segment. This layer prevents
that comprises the papillary dermis, between the epider- the destruction of living keratinocytes by environmental factors
mal folds and the periadnexal dermis surrounding ad- and reduces or minimizes water evaporation, maintaining a
nexal structures. The papillary dermis is characterized by liquid environment to preserve skin structural integrity in the
thin collagen bundles interspersed with elastic fibers, fre- face of frequent mechanical trauma. The epidermal pigmentary
quent fibrocytes, abundant matrix, and a rich vascular system protects the skin against the damaging effect of solar
network composed predominantly of capillaries. The re- radiation in humans and, in conjunction with the follicular
ticular dermis is composed predominantly of thick colla- pigmentary system, determines hair and skin color that play an
gen bundles and elastic fibers and a lower concentration important role in social communication and camouflage in
of stromal matrix, with comparatively fewer fibrocytes; many mammalian species. The epidermal and dermal immune
there are also blood vessels, and adipocytes that extend elements provide defense against biological insults, and they
upward from the subcutaneous fat. are also involved in the integration of the response to foreign
The skin immune system is composed of resident, re- and self-antigens through interactions with the central immune
cruited, and recirculating cell populations (7). The resident system. Immune responses are involved in the reaction to viral
population is constitutively expressed in the skin under or microbial infections, or to cancer development; dysregulated
physiological conditions. This is represented by keratino- immune responses may be pathogenic in autoimmune diseases.
cytes, fibroblasts, vascular and lymphatic endothelial cells, The adnexal organs are epidermally derived structures
mast cells, tissue macrophages (histiocytes), T lymphocytes, that extend into dermis and subcutis. Their functional role is
and dendritic cells. The recruited population comprises pleiotropic by participating in the formation of hair shafts
monocytes, basophilic, neutrophilic, and eosinophilic gran- from hair follicle, serving protective, thermoregulatory, and
ulocytes, as well as mast cells and T and B lymphocytes. The sensory (touch) functions, as well as being involved in social
recirculating cell population is represented by dendritic cells, communication. The secretion of eccrine, apocrine, and se-
natural killer cells, and T lymphocytes. Recruited or recir- baceous glands is important for thermoregulation, for pres-
culating cells reach the skin via circulation. ervation of the integrity of the physical barrier, for regulation
The vasculature is arranged into a superficial (subpapil- of electrolyte balance, and for secretion of the pheromones
lary) plexus, located in the upper reticular dermis, and a deep and odorant-affecting behavior. The dermis, in addition to its
plexus positioned in the lower reticular dermis (1– 4). These structural role, is involved in mechanical protection and ther-
plexuses are connected by communicating blood vessels, moregulation via its rich vascular network. The skin also
which are most numerous in the upper dermis and around provides the sensory reception for touch, pressure, vibration,
folliculosebaceous and eccrine units. The vascular network temperature, pain, and pleasure through a neural network
provides rich capillary supply for the dermal papillae and comprised of specialized receptors and free nerve endings.
periadnexal dermis. A lymphatic network accompanies the Finally, the skin, as a regulator of metabolism, transforms
vascular bed, although it is a functionally separate entity. various hormones and can also inactivate potentially harm-
The skin contains an extensive neural network represented ful substances of exogenous or endogenous origin.
by cholinergic and adrenergic nerves and by myelinated and
unmyelinated sensory fibers (1, 3, 4, 33, 34). The autonomic III. Skin as a Target for Neuroendocrine Signals
nerves supply arterioles, glomus bodies, hair erector mus-
cles, and apocrine and eccrine glands. The terminal endings Skin resident and circulating immune cells express recep-
of sensory fibers are either surrounded by histologically dis- tors for neuropeptides and neurotransmitters identical to
tinctive structures, such as Pacini and Meissner’s corpuscles, those expressed in the central neuroendocrine systems. Ex-
Ruffini organs, Merkel disks, and mucocutaneous end or- amples of those receptors and their expression sites are listed
gans, or supply directly individual Merkel cells. A rich net- in Table 1. Clinical observations made in diverse endocrine
work of free sensory endings surround and penetrate hair disorders associated with cutaneous changes also confirm
follicles, pilosebaceous units, eccrine and apocrine glands, that the skin is a target for hormones, neurohormones, and
papillary dermis, and epidermis. The sensory and autonomic neurotransmitters (3– 6, 12, 16 –21, 35–38). That the skin is

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460 SLOMINSKI AND WORTSMAN Vol. 21, No. 5

TABLE 1. Selected hormone and neurotransmitter receptors expressed in keratinocytes and melanocytes

Cell type Receptor repertoire


Keratinocytes CRH-R1, MC1-R, ␮- and ␨-opioid-R, PRL-R, LH/CG-R, GH-R, CGRP-R, VIP-R, neurokinin-R, class II
PTH/PTHrP-R, vitamin D-R, androgen-R, estrogen-R, glucocorticoid-R, mineralocorticoid-R,
muscarinic-R, nicotinic-R, adrenoreceptors, glutamate-R, gastrin-releasing peptide-R, NPY-R,
purinoreceptors, H1 and H2 histamine-R, somatostatin-R (?), bombesin-R, (?)
Melanocytes CRH-R1, MC1-R, LH/CG-R, GH-R, CGRP-R, VIP-R, vitamin D-R, androgen-R estrogen-R, glucocorticoid-
R, adrenoreceptors, muscarinic-R, H2 histamine-R
R, Receptor; (?), possible expression.

also a target of neural responses is supported by studies and mouse skin (65, 66), precise cell compartment(s) assign-
showing neural contributions to the etiology and clinical ment will require further testing; possible expression sites
manifestations of inflammatory skin diseases and vitiligo include adipocytes, keratinocytes, and melanocytes (63– 66).
(3, 4, 33, 34, 38, 39). The MC receptors are activated by ACTH, and by ␣-, ␤-
and ␥-MSH; ligand affinity varies according to receptor type
A. CRH and urocortin receptors (CRH-R) and mammalian species (5, 8, 17, 61, 70). Signal transduction
through MC1-R, MC2-R, and MC5-R has been linked to ac-
This group comprises the G protein-coupled membrane-
tivation of adenylate cyclase (5, 8, 17, 61, 67– 69).
bound CRH-R1 and CRH-R2 receptors (5, 40, 41), whose gene
expression was recently documented in human and rodent The best recognized phenotypic effect of the POMC-
skin (5, 18, 40, 42– 46). CRH-R1 expression has been detected derived ACTH and MSH peptides is the stimulation of mel-
in epidermal and follicular keratinocytes, melanocytes, and anogenesis and its switching from pheo- to eumelanogenesis
mast cells (5, 44, 46 – 49), and it is possible that these cells may (5, 8, 16, 17, 61, 67–72), which can also be documented clin-
coexpress CRH-R2 (5, 44, 46, 50, 51). While specific CRH ically (3–5, 8, 67, 72). There is a general agreement that ACTH,
binding sites were additionally seen in dermal fibroblasts, ␣-MSH, and ␤-MSH have the strongest melanogenic activity
endothelial cells, and smooth muscle of blood vessels (5, 40, (8, 16, 67– 69). ␥-MSH peptides have low intrinsic melano-
44, 46, 52–54), it remains to be tested whether these binding genic activity in human normal melanocytes and rodent ma-
sites represent CRH-R1, CRH-R2, or coexpression of both lignant melanocytes (70, 71), similar to findings in frog and
receptors. Signal transduction through cutaneous CRH re- lizard melanophores (8, 67, 68, 73). However, it is possible
ceptors is linked to stimulation of cAMP production and that selected ␥-MSH peptides such as ␥2 and ␥3 could still
increase of cytosolic Ca levels (46, 47, 50, 51). It remains to be modulate pigmentation indirectly, modifying cellular re-
tested whether other pathways coupled to different receptor sponses to the other melanotropins (71). Studies in cultured
subtypes specific for skin cells are also activated (46, 50). normal and malignant melanocytes show that MSH and
CRH and urocortin have a recognized role in skin patho- ACTH, acting via cAMP-dependent pathways (5, 8, 16, 17, 61,
physiology through their actions on the skin immune system 67– 69, 72, 74 –79), stimulate the expression and activity of
(5, 40, 48, 55–59). Thus, in the periphery, CRH can act as a enzymatic, structural, and regulatory proteins involved in
proinflammatory agent (48, 55, 56) and, together with uro- melanogenesis (5, 8, 67– 69). Depending on species and cel-
cortin, induces degranulation of mast cells (48, 57). However, lular genotype, MSH and ACTH can inhibit or stimulate
antiinflammatory effects have been also demonstrated in proliferation of malignant melanocytes (8, 67– 69, 72, 74 –78).
models of tissue injury, e.g., in thermally injured skin where However, most authors agree that in normal human mela-
local injection of CRH has an antiedema effect independent nocytes, ACTH and MSH act as stimulators of cell prolifer-
of hypothalamus-pituitary-adrenal (HPA) axis function, and ation (8, 69, 79), dendrite production (5, 8, 67– 69, 74), and
in doxorubicin-induced eye lid inflammation that is reduced melanocyte migration (8) and decrease expression of inter-
in severity by pretreatment of the eyelid with CRH (58 – 60). cellular adhesion molecule-1 (ICAM-1) (80).
In addition, CRH has antinociceptive activity and accelerates Epidermal, adnexal, vascular, and dermal structures rep-
wound healing (58 – 60). CRH and urocortin also inhibit pro- resent additional targets for POMC peptides (5, 17, 35, 61–
liferation of keratinocytes (51) and either stimulate or inhibit 64). Thus, ␣-MSH can modify proliferation and differentia-
melanoma cell proliferation depending on culture conditions tion of keratinocytes as well as their immune activity and
(Refs. 46 and 49 and A. Slominski and B. Zbytek, unpublished regulate activity of dermal fibroblast (5, 17, 64, 81, 82). In
data). endothelial cells, ␣-MSH may play a crucial role decreasing
their adherence and the transmigration of inflammatory
B. Melanocortin receptors (MC-R) cells, a prerequisite step for immune and inflammatory re-
The membrane-bound G protein-coupled melanocortin re- actions. ␣-MSH and ACTH have strong immunomodulating
ceptors of type 1, 2, and 5 (MC1-R, MC2-R, MC5-R) have been activity in the skin that results in an overall immunosup-
identified in the skin (5, 8, 17, 61– 69). MC1-R was detected pressive effect (5, 17, 64, 82). For example, ␣-MSH acts as
in melanocytes, keratinocytes, sebocytes, fibroblasts, endo- antagonist to interleukin-1 (IL-1) suppressing production of
thelial cells, Langerhans cells, and dermal immune cells, proinflammatory cytokines while it induces production of
while MC5-R was detected in the epithelial cells of eccrine, the immunosuppressive cytokine IL-10. ␣-MSH is also ca-
apocrine, and sebaceous glands (5, 8, 17, 61– 64). Although pable of suppressing accessory molecule expression on an-
expression of the MC2-R gene has been detected in human tigen-presenting cells and may thereby serve as one of the

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October, 2000 NEUROENDOCRINOLOGY OF THE SKIN 461

signals responsible for anergy or tolerance induction (17, 64, hyperpigmentation, eccrine and apocrine hyperhidrosis,
82). increased sebum secretion, growth of pedunculated fibro-
In addition to the regulation of hair pigmentation, ␣-MSH mas, and thickening and hardening of the nails (1–3, 36, 37,
and ACTH have other actions on adnexal structures (5, 17, 68). Transgenic mice overexpresssing GH show skin over-
35, 62, 83, 84). For example, in mink and mice, ACTH acts as growth with increased dermal thickness, significant der-
inducer of anagen development (85, 86), whereas in mouse mal fibrosis, and replacement of subcutaneous adipose
anagen skin it induces premature onset of catagen (83). tissue by fibrous tissue (97).
ACTH and ␣-MSH also influence sebaceous gland function
(35, 84): ␣-MSH specifically stimulates sebum secretion and
lipogenesis in cutaneous sebaceous glands, enhancing wax E. PRL and LH/CG receptors (LH/CG-R)
and sterol ester biosynthesis, and stimulating production
Receptors for the pituitary hormones PRL, LH, and human
and release of female sex attractant odors and of male ag-
CG (hCG) are also expressed in the skin (98 –103). PRL re-
gression-promoting pheromones (by specialized preputial
ceptors have been localized in rat epidermal and follicular
glands) (35). ␣-MSH and perhaps ACTH may be important
keratinocytes by in situ hybridization (98) and in ovine der-
in overall rodent skin thermoregulation, by preventing over-
mal papilla fibroblasts and follicular keratinocytes with a
wetting of hairs, and in behavior regulation through its ac-
radioligand binding assay (99). PRL binding sites exhibiting
tion on nonspecialized and specialized sebaceous glands (35,
high affinity for the ligand were identified in membrane
84). It is likely that MSH and ACTH peptides also affect
preparation from mink skin; the highest concentration of
function of human sebaceous glands.
binding sites was found during the winter fur growth cycle
(100). PRL stimulation of cultured human keratinocytes pro-
C. Opioid receptors liferation has been linked to the expression of high-affinity
PRL binding sites on the cell surface (101). PRL can directly
␮-Opioid receptors, which bind with high-affinity ␤-
and indirectly modulate the hair growth, shedding, and
endorphin, were detected in cultured human epidermal ker-
molting cycle of furry animals, whereas in humans hyper-
atinocytes (87). Further investigations using in situ hybrid-
prolactinemia has been associated with hirsutism (3, 31, 104 –
ization and immunocytochemistry on skin biopsy specimens
106). It has also been proposed that PRL participates in the
showed that the receptors are localized to keratinocytes in
regulation of sebaceous gland activity, since acne vulgaris
the epidermis and outer root sheath of the hair follicles, to the
can be associated with idiopathic hyperprolactinemia in the
peripheral epithelial cells in sebaceous glands, and to the
absence of altered androgen concentrations (3, 106). PRL has
secretory component in sweat glands (87). The related ␨-
potent immunomodulatory properties (107), suggesting that
opioid receptor that binds enkephalins with high affinity has
it can also regulate functions in the skin immune system.
also been detected in human and mouse epidermal keratin-
Normal human skin also contains the mRNAs for the
ocytes (88). Met-enkephalin has been shown to inhibit pro-
LH/CG-R and a 66-kDa protein capable of binding 125I-hCG
liferation of mouse epidermal keratinocytes in vivo, in a cir-
(102). These receptors were detected in the epidermis, inner
cadian pattern (88), and both met- and leu-enkephalins can
and outer root sheaths of the anagen hair follicle, sebaceous
inhibit differentiation of human keratinocytes in vitro (89). In
glands, and eccrine glands (103). Testing for expression of
addition, ␤-endorphin and enkephalins have antinociceptive
FSH receptors in normal human skin found it to be below the
and immunomodulatory properties (7, 24, 25, 27, 28).
level of detectability (103).

D. GH receptor (GH-R)
F. Neurokinin receptors (NK-R)
The GH-R has been detected in human and rodent skin in
epidermis, hair follicle, eccrine glands, dermal fibroblasts, Expression of the G protein-coupled neurokinin receptors
adipocytes, and in Schwann and muscle cells (90 –93). Tran- NK-1R, NK-2R, and NK-3R has been reported in human and
scription of the GH-R gene has also been detected in cultured rodent skin (38, 108); however, others have detected only
human melanocytes (91). These findings suggest that epi- NK1-R in extracts from human skin (109). Either substance
dermal, adnexal, and dermal cell populations can be direct P (SP) or neurokinins A and B (NKA and NKB) could activate
targets for GH. For example, GH can stimulate differentia- these receptors, through signal transduction pathways in-
tion of rat sebocytes and modify melanocyte proliferation volving adenylate cyclase and phospholipases C and A2 (33,
(94, 95). However, the phenotypic effects could also arise 34, 38). Human and rodent keratinocytes and endothelial
from an indirect effect such as the stimulation of cutaneous cells express NK-1R to NK-3R, and mast cells, fibroblasts,
cells to produce insulin growth factor-1 (IGF-1). and Langerhans cells express NK-1R (38). Activation of these
The cutaneous phenotypic effects of GH have been thor- receptors stimulates proliferation of keratinocytes, fibro-
oughly described in patients with acromegaly, whose skin blasts, and endothelial cells and neovascularization (4, 7, 33,
thickness increases considerably and acquires a doughy 34, 38, 108 –113). NKA and SP stimulate mast cells release of
texture (1–3, 36, 37, 68). This effect is accompanied by histamine and tumor necrosis factor-␣ (TNF␣), and keratin-
increased fibroblasts activity and dermal glycosaminogly- ocyte and endothelial cell function with production and re-
cans deposition that promotes water retention (96). Ad- lease of proinflammatory cytokines, and expression of ad-
ditional cutaneous signs of acromegaly are acanthosis nig- hesion molecules (7, 33, 34, 38, 108 –115). SP stimulates hair
ricans, hypertrichosis with exception of the beard region, growth in rodents (116).

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462 SLOMINSKI AND WORTSMAN Vol. 21, No. 5

G. Calcitonin gene-related peptide receptor (CGRP-R) J. Miscellaneous neuropeptide receptors


There is functional evidence that the G protein-coupled Somatostatin is known to affect skin immune functions
receptor CGRP-R is expressed in skin cells (3, 4, 7, 33, 38, 108, and basal secretion of histamine and, thus, immune cells and
110 –114, 117–120). CGRP is a potent vasodilator of small and keratinocytes probably express the corresponding receptors
large vessels, at least partly through direct activation of ar- (38, 110 –112, 133). Similarly, the inhibition of cAMP pro-
teriolar smooth muscle cell receptors. CGRP also increases duction by neuropeptide Y (NPY) in human keratinocytes,
vascular permeability, producing dermal edema through in- the stimulation of keratinocyte DNA synthesis by bombesin,
direct activation of mast cells or through stimulation of nitric and the acceleration of skin wound healing by TSH (12, 33,
oxide (NO) production by endothelial cells with consequent 38, 110 –112, 117) suggest that specific receptors for these
vasodilatation (4, 33, 38, 108, 114). CGRP stimulates endo- hormones may be also expressed in skin. There are, in fact,
thelial cell, keratinocyte, and melanocyte proliferation (117, data showing that the gene coding for the TSH receptor is
119). Stimulation of keratinocyte proliferation has been expressed in adipocytes and fibroblasts (134). Receptors for
linked to direct activation of adenylyl cyclase activity (117), bombesin and somatostatin have been shown in dermal fi-
and CGRP induces keratinocyte production and release of broblasts (33, 38, 111, 112).
promelanogenic factors (120). CGRP modifies the activity of
the skin immune system (7, 38, 110 –114, 118). K. PTH and PTH-related protein (PTHrP) receptors
Dermal fibroblasts express class 1 PTH/PTHrP receptors,
H. Vasoactive intestinal peptide receptor (VIP-R) which respond to PTH or the PTHrP signal by increasing
cAMP, production of cytokines and keratinocyte growth fac-
VIP-Rs are present in skin, and their activity is linked to
tor (KGF) (135, 136); however, the same receptor is not de-
G protein-coupled stimulation of adenylyl cyclase activity
tected in keratinocytes (135, 137–139). Nevertheless, PTHrP
with cAMP production (3, 4, 7, 33, 38, 108, 110 –113, 117, 118).
has direct epidermal biological activity stimulating keratin-
VIP biding sites have been characterized in malignant human
ocyte proliferation and differentiation both in vitro and in
melanocytes (121), where VIP stimulates cAMP production
vivo, and hair follicle formation (15, 140, 141). The keratin-
(122).VIP also stimulates keratinocyte proliferation and
ocyte intracellular activation pathway differs from that stim-
sweat production (4, 38, 117). Peptide histidine-methionine
ulated by class I receptors; PTHrP, while producing intra-
(PHM) and GH releasing factor (GFR) have stimulatory ef-
cellular calcium accumulation and protein kinase C
fects on keratinocyte cAMP production and cell proliferation,
stimulation, does not stimulate adenylate cyclase; instead it
thought to be mediated through the VIP-R (38, 117). Indi-
activates the phospholipase C pathway (138, 139, 142, 143).
rectly, VIP also participates in the wheal and flare reaction
These PTH/PTHrP class II keratinocyte receptors have been
through the activation of mast cells histamine release,
partially characterized and found to also respond to PTH
or through NO-induced vasodilatation (3, 4, 7, 33, 38, 108,
(138, 139, 143). PTHrP can indirectly regulate functional ac-
111, 112).
tivity of the epidermis through the stimulation of KGF pro-
duction by dermal fibroblasts (136). Furthermore, PTHrP can
I. Neurotrophin (NT) receptors play a role during wound healing, helping restore epidermal
homeostasis (144). Studies on the PTHrP knockout mouse
Both human and rodent skin express transmembrane re- model, and in mice overexpressing the peptide in the skin,
ceptor proteins of the tyrosine kinase (Trk) and p75 pan- document an important role of PTHrP on epidermal function
neurotrophin (p75NTR) families, which show high and low and hair formation (15, 141).
affinity for neuron growth factor (NGF), respectively (33, 38,
108, 123–131). The high-affinity receptors for NGF and NT4 L. Vitamin D receptor (VDR)
include TrkA and TrkB; TrkC serves as a high-affinity re-
ceptor for NT3, which also binds, but with low affinity, to Receptors for the active form of vitamin D [1,25-dihy-
TrkA and TrkB. The receptors for the Trk family and for droxyvitamin D (1,25-(OH)2D or calcitriol] are expressed in
p75NTR are expressed in epidermal and follicular keratin- human and rodent epidermal and follicular keratinocytes
ocytes, epidermal melanocytes, specialized dermal fibro- (13, 145–151). In the mouse, hair cycle-dependent VDR ex-
blasts, mast cells, immunocytes, and cutaneous nerves (7, 33, pression has been reported: it is stronger in mid and late
38, 108, 123–130). NGF stimulates melanocyte dendrite for- anagen and in catagen and weaker in the telogen and early
mation and prolongs melanocyte survival after UV damage anagen phases of hair growth (146). VDRs serve as targets
(123, 124). NGF and other neurotrophins can regulate ker- mediating calcitriol induction of keratinocyte differentiation
atinocyte proliferation and differentiation (123, 125, 128 – and inhibition of cell proliferation (13, 148). Because of these
130), functions that in the mouse appear to be coordinated properties, vitamin D derivatives are being used therapeu-
with the hair cycle (128). Lastly, NGF and other neurotro- tically (topically) in psoriasis (3, 13, 14). The presence of
phins can act as mast cells secretagogs and can modulate alopecia in some forms of vitamin D-resistant rickets with
dermal fibroblasts and dermal immune cells function (7, 33, decreased expression of VDR in dermal papilla cells indicates
38, 108, 123–130). NGF and neurotrophins may have a phys- a role in hair growth (13, 150). Some authors have identified
iological role in hair cycle and hair follicle morphogenesis VDRs in human melanocytes and observed a modulatory
(128 –130, 132), whereas NGF may protect human keratino- effect of 1,25-(OH) 2D on melanogenesis (8, 151). This ob-
cytes from UVB-induced apoptosis (125). servation has not been confirmed universally (152). Skin

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October, 2000 NEUROENDOCRINOLOGY OF THE SKIN 463

immune cells may also express VDRs because of the finding skin (3, 4, 12, 166 –168, 170 –173). ERs have been detected
of constitutive immunosuppressive activity for 1,25-(OH) 2D variably, depending on the sensitivity method and presence
(153). Patients with mutations of VDR present with hypocal- or absence of pathology, in epithelial cells of epidermis, hair
cemia, rickets, and significant cutaneous involvement ex- follicle, sebaceous, eccrine and apocrine glands, in melano-
pressed as sparse body hair and, sometimes, total alopecia cytes, and in dermal fibroblasts. Thus, both estrogens and
that includes the eyebrows and eyelashes (150). In the latter androgens regulate hair growth, sebaceous gland function,
subjects, VDR gene mutations result in premature stop sig- proliferation and differentiation of epithelial cells of the epi-
nals or abnormal DNA binding and marked resistance to dermis and adnexa, functional activity of dermal fibroblasts
calcitriol therapy (150). Experiments performed on mice and fibrocytes, wound healing, and skin immune cells ac-
treated with topical calcitriol show normal hair regrowth tivity. There are also data showing that androgens and es-
after chemotherapy-induced alopecia (147). trogens can modulate proliferation and melanogenesis in
cultured melanocytes (169 –171). Lastly, transgenic male
M. Glucocorticoid and mineralocorticoid receptors
mice overexpressing GH show overgrowth of the skin that
is androgen dependent, e.g., it is not observed in females or
Glucocorticoid receptors (GRs) are members of the super- in castrated males (97).
family of trans-acting transcriptional factors and are widely Clinical signs of androgen excess include acne, hirsutism,
expressed in all skin compartments (3, 4, 12, 31, 154 –157). and androgenic alopecia (3, 36, 37, 163, 164). Acne results
More specifically, GRs are expressed in epidermal and fol- from follicular hyperkeratinization, increased sebum pro-
licular keratinocytes, epithelial cells of eccrine and apocrine duction, and from the release of lipases and proinflammatory
glands, sebocytes, melanocytes, immune cells of epidermis mediators by Propionicum acnes. In these conditions, an-
and dermis, dermal fibroblasts, and smooth muscle (154 – drogens [mainly dihydrotestosterone (DHT) and to a lesser
157); activation of these receptors regulates or modulates degree testosterone] mediate the increased sebum produc-
specific functions in the corresponding cells. The role of tion and follicular hyperkeratinization (3, 37, 163, 164). Hir-
glucocorticoids is best emphasized by the skin changes as- sutism and androgenic alopecia are associated with in-
sociated with hypercortisolism (3, 36, 37). In such states there creased production of DHT within the dermal papilla of
are alterations in body fat distribution, general atrophy of the androgen-responsive hair follicles of the face, chest, genital
skin, impairment of wound healing, easy bruisability, mild skin, and scalp (3, 12, 31, 37, 163). Conversely, in males with
acanthosis nigricans, acne, hirsutism, and alopecia. A glu- androgen deficiency, the skin remains thin and fine; seba-
cocorticoid direct inhibitory effect on hair growth has been ceous and apocrine glands and sexual hair follicles remain
well documented in animal models (31). It must also be dormant; beard, axillary, and pubic hair do not develop and
emphasized that glucocorticoids, whether administered top- neither does androgenic alopecia; and there is also a general
ically or orally, are potent drugs used in the treatment of decrease in skin pigmentation (3, 37, 163). Increased estrogen
inflammatory skin diseases (3). levels, for example during pregnancy, can lead to hyperpig-
Most recently, mineralocorticoid receptors (MRs) have mentation of nipples, areolae, genital skin, and facial skin (3).
been detected in keratinocytes of the epidermis and hair The latter, known as melasma, is exacerbated by sun expo-
follicle and in sweat and sebaceous glands of human skin sure (3). In addition, preexisting nevi and ephelides darken,
(158). The same cutaneous structures also expressed 11␤- and telangiectasia, spider angioma, and palmar erythema
hydroxysteroid dehydrogenase (11HSD), which converts may develop (3, 37).
glucocorticoids to their inactive metabolites, thereby allow- The presence of actual ERs in malignant melanocytes has
ing the binding of aldosterone to MRs at much lower pre- been questioned (174). However, studies with normal cul-
vailing levels (158, 159). tured melanocytes have demonstrated both the presence of
receptors and phenotypic effects on cell proliferation (171).
Nevertheless, the reports are truly conflicting as regards the
N. Androgen and estrogen receptors
estrogen effect on melanogenesis. Thus, while some have
Sex steroid receptors belong to the superfamily of trans- reported stimulation of tyrosinase activity and melanin syn-
acting transcriptional factors, similar to glucocorticoid re- thesis by estrogens (170), others have shown an opposite
ceptor (GR) and mineralocorticoid receptor (MR) (36, 68). inhibitory effect (171). These contradictory results indicate
They are widely distributed in all skin compartments, and the need for additional work on the role of estrogens in
their density and expression level vary depending on ana- melanocyte functions.
tomic site and gender (3, 4, 12, 160 –173). The well recognized
androgen effects on hair growth and sebaceous gland func- O. Thyroid hormone receptors
tions are related to expression of the corresponding androgen
receptors (ARs) in epithelial cells of those adnexal structures The skin is a recognized target for T3 (3, 4, 12, 31, 36, 37,
and in specialized dermal papilla fibroblasts that regulate 157, 164, 175, 176). This hormone is involved in the process
hair morphogenesis (161–165). ARs are also expressed in of epidermal differentiation and increases its responsiveness
other adnexal structures, in epidermal keratinocytes and me- to growth factors. It also participates in the function of se-
lanocytes, dermal fibroblasts, and resident and circulating baceous, eccrine, and apocrine glands, in hair growth, and in
cells of the skin immune system (3, 4, 12, 31, 160 –165, 169). the production of proteo- and glycosaminoglycans by dermal
Similar to ARs, estrogen receptors (ERs) are also expressed fibroblasts. All of these effects are probably mediated by
in the epidermal, adnexal, and dermal compartments of the interactions with the specific thyroid hormone receptors

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464 SLOMINSKI AND WORTSMAN Vol. 21, No. 5

(TRs) that serve as transcriptional regulators. In fact, thyroid and their activation induces vasoconstriction and decreases
hormone receptors (c-erb-A) were detected by RT-PCR in vascular permeability (4, 190, 191). Since the melanoma cell
human skin (177), and c-erbA␤ and c-erbA␣ mRNAs were phenotype can be modified by adrenergic agonists, it is pos-
detected in dermal fibroblasts, consistent with T3 binding to sible that normal mammalian melanocytes may express ad-
fibroblast nuclear extracts (178). Since T3 may have an in- renergic receptors, similar to pigment cells of other verte-
hibitory effect on melanogenesis in malignant melanocytes, brates (8, 66, 192). The ␤1, ␤2, and ␤3 adrenoceptors are also
it is likely that TR is also expressed in melanocytes (179). present on adipocytes (193).
A potential role for thyroid hormones in the regulation
of skin function is suggested by its changes in hyper- and R. Glutamate receptors
hypothyroidism (3, 36, 37). In the former, the skin changes
include erythema, palmoplantar hyperhidrosis, acropathy, Immunocytochemical studies performed on rat skin dem-
and infiltrative dermopathy. Graves’ disease also may be onstrated the presence of the G protein-coupled metabotropic
associated with generalized pruritus, chronic urticaria, alo- receptors of the ionotropic glutamate-gated ion channels such
pecia areata, vitiligo, and diffuse skin pigmentation. In hy- as the N-methyl-d-aspartate (NMDA) and ␣-amino-3-hydroxy-
pothyroidism, the skin is cool, dry with pasty appearance; 5-methyl-4-isoxazole propionate (AMPA) types of glutamate
the epidermis is thin and hyperkeratotic; alopecia may de- receptors in basal epidermal keratinocytes (194). In addition to
velop, and there is diffuse myxedema. In contrast to the receptor expression, the specific glutamate transporters have
pretibial myxedema present in hyperthyroidism, the gener- been also detected. Thus, EAAC1 was found in basal keratin-
alized myxedema of hypothyroidism is reversible with thy- ocytes, GLT-1 in suprabasal keratinocytes, and the AMPA-type
roid hormone therapy (37). receptor clustering protein, GRIP, in basal keratinocytes (194).
In the same rat model, epidermal expression levels of the
NMAD receptor and the EAAC1 glutamate transporter were
P. Cholinergic receptors significantly related to wound healing and embryogenesis. Cul-
Grando and associates (20, 180 –182) found that human tured human keratinocytes have shown expression of mRNAs
keratinocytes express both nicotinic and muscarinic recep- for the NMDAR1 subunit and for GRIP (194).
tors in a differentiation-dependent manner. Specifically, hu-
man keratinocytes were found to express the ␣3, ␣5, ␣6, ␣7, S. Serotonin receptors
␤1, ␤2, and ␤4 nicotinic receptor subunits (20, 180, 181). The potential presence of serotonin receptors in the skin is
Immunocytochemistry studies further showed that the num- suggested by the local effects of serotonin, e.g., pro-edema,
ber and subunit composition varies according to stage of vasodilatory, proinflammatory, and pruritogenic (3, 4, 34,
epidermal keratinocyte differentiation (20, 181). The nicotinic 115, 195, 196). In mouse skin, serotonin-induced vascular
receptors on keratinocytes represent functional ion channels permeability is mediated by the activation of 5-hydroxytryp-
mediating the influx of Na⫹ and Ca⫹2, and the efflux of K⫹, tamine type 1 (HT1) and HT2 receptors (197). The prurito-
being thus essential for keratinocyte viability (20, 180, 181). genic effect of serotonin may be mediated through direct
Activation of nicotinic receptors stimulates keratinocyte mo- activation of HT3 receptors or indirectly through mast cells
tility and differentiation (20, 180, 181). (7, 27, 34, 198). Cutaneous expression of 5-HT2A receptors
Muscarinic receptors of several subtypes have been de- was detected in unmyelinated axons at the dermal-epider-
tected in vitro and in vivo in epidermal keratinocytes (20, 181, mal junction and in the nerve endings of Pacinian corpuscles
182). The subtypes expressed include the m1, m3, m4, and m5 (199). Because of serotonin proinflammatory activity, it is
types, with both timing and level of expression being de- likely that cells of the skin immune system will also express
pendent on keratinocyte differentiation stage (20, 181, 182). the HT receptors generally found in the immune cells (7, 27).
Muscarinic receptors have been characterized also in malig- Such mechanism would explain the initiation of T cell-
nant human melanocytes (183, 184), and there is strong ev- dependent contact sensitivity by serotonin released from
idence for their expression in normal melanocytes (Grando human platelets (200), and also the release of prostaglandin
et al., unpublished observation). E2 from rat skin in vitro (201). Since serotonin can stimulate
epidermal keratinocyte proliferation in organ culture, these
Q. Adrenergic receptors cells may also express HT receptors (202).
Radioligand binding studies have shown cutaneous ad- T. Histamine receptors
renergic receptors, with epidermal keratinocytes and eccrine
epithelial cells expressing predominantly the ␤2 adrenore- After its release from mast cells, basophils, and platelets,
ceptors (4, 21, 185–187). In situ binding assays have further histamine has pleiotropic phenotypic effects in the skin
identified ␣1- adrenoreceptors in the epidermis (188). Stim- through interactions with H1, H2, and H3 receptors (3, 7, 115,
ulation of ␤-adrenergic receptors in epidermal keratinocytes 203). Histamine’s most prominent cutaneous effects are on
results in increased cAMP production, calcium influx, and the local vascular and immune systems, supporting the use
stimulation of keratinocyte differentiation (3, 4, 21, 187). of antihistamine drugs for the treatment of pruritus, urti-
␤-Receptors are expressed in inflammatory cells of the der- caria, and angioedema (3, 7, 115, 195). Histamine receptors
mis (185), thus explaining the ␤2-adrenoreceptor agonists are expressed in the dermal compartment on immunocytes,
inhibition of proinflammatory TNF␣ release (189). ␣- And endothelial cells, blood vessels, smooth muscle, fibroblasts,
␤-adrenoreceptors are expressed in dermal blood vessels, and nerve endings (3, 7, 115, 195, 203), whereas in the epi-

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October, 2000 NEUROENDOCRINOLOGY OF THE SKIN 465

dermis, H1 and H2 receptors are expressed on keratinocytes IV. Skin as a Source of Hormones and
(204 –207). Epidermal melanocytes express H2 receptors Neurotransmitters
(208). Activation of keratinocyte H2 receptors affect prolif-
Hormones and neurotransmitters produced by epidermal
eration and differentiation via activation of the adenylate
and adnexal structures and dermal cells are listed in Table 2.
cyclase/phospholipase C pathway with associated increases
Neuropeptides released by cutaneous nerve endings or pro-
in intracellular calcium levels (204, 205). In the same cell
duced by skin are listed in Table 3. The production of vitamin
system, activation of the H1 receptor enhances UVB-induced
D is covered separately because it is synthesized in the skin,
IL-6 production (206), whereas H1 receptor antagonists in-
and its systemic effects have been well characterized.
hibit ICAM-1 expression (207). Activation of the H2 receptors
on melanocytes stimulates melanogenesis (208). Thus, both
the dermal and epidermal compartments are clear targets for A. PTHrP
histamine, regulating cellular functions not directly con- PTHrP is a protein made ubiquitously throughout the
nected with the previously described proinflammatory ef- body and expressed most intensely in embryonal and fetal
fects of this mediator. Of great interest is the proposed role tissues (15). Its gene is encoded in chromosome 12 and, when
for the mast cell as a coordinator of immune, neural, and expressed and processed in human keratinocytes, yields
endocrine activity on the central level and peripheral organs three or more isoforms (5, 137). Three transcripts that have
(115, 203); in this context the cutaneous actions of histamine been best characterized are 139, 141, and 173 amino acids
through specific receptors would also be addressed at coor- long (137). The N-terminal region of PTHrP shows a high
dinating the local cutaneous neuroendocrine system re- degree of homology with PTH, with which it shares 8 or 9 of
sponses (203). the first residues. Likewise, PTHrP can bind to the classic
bone and renal receptors for PTH (type I), producing hy-
U. Miscellaneous receptors percalcemia (219).
In the skin, PTHrP is highly expressed in the granular layer
A number of studies suggest that epidermal keratinocytes of the epidermis and outer root sheath of the hair follicle and
express purinoreceptors that, when activated by adenosine at much lower levels in basal keratinocytes and melanocytes
or adenine nucleotides, will stimulate cAMP and IP3 pro- (15, 220). Pathologically, PTHrP is frequently expressed in
duction, respectively (209, 210). Purinoreceptor activation squamous carcinomas and in their corresponding cutaneous
inhibits keratinocyte proliferation (211). Functionally active form (15, 143). Expression of PTHrP has also been reported
adrenomedullin receptors (AM-R), which are G-protein in metastatic melanoma (221, 222). In addition, during
linked and coupled to adenylyl cyclase activity, have been wound healing PTHrP is produced by granulation tissue
identified in epithelial cells of epidermis, hair follicle, seba- cells that include myofibroblasts and infiltrating macro-
ceous and eccrine glands, and in melanoma cells (212). AM phages (144). It is of interest that PTHrP is the main cause for
binding sites have been characterized in cultured keratino- the syndrome of humoral hypercalcemia of malignancy
cytes and in melanoma cells; in the latter system AM stim- (HHM) and that it is produced predominantly by squamous
ulates DNA synthesis (212). Calcium sensing receptors iden- cell tumors (223). However, cutaneous squamous cell carci-
tical to those found in the parathyroid glands have been nomas, which have a high incidence of about 39/100,000,
identified in cultured normal human keratinocytes (213). may have resulted in only a few documented cases of HHM
There is also experimental data suggesting the existence of (223). The reason for this discrepancy is unclear but may be
receptors for l-tyrosine and l-DOPA (214), since both l- related to lower levels of expression, release of mostly inac-
tyrosine and l-DOPA can act as regulators of melanogenesis tive fragments, or of inability of PTHrP molecules to cross the
(10, 23), and l-DOPA can suppress lymphocyte activity (215). basement membranes and reach the systemic circulation
Finally, the modulatory effect of melatonin on keratinocyte (219). Presumably, such a barrier is broken in some cases of
proliferation and inhibition of melanogenesis suggests that advanced squamous cell carcinoma of the skin that develop
melatonin receptors are expressed also in mammalian skin hypercalcemia. HHM associated with increased serum levels
(216 –218). Nevertheless, the evidence is based solely on the of PTHrP has also been described in metastatic human mel-
detection of melatonin binding sites, while specific receptors anoma (221); and, in at least one case, clear evidence is
for melatonin remain to be characterized. In lower verte- provided that melanoma cells themselves have been the
brates, skin melatonin receptors are well characterized, and source of PTHrP (222). The reported patient had no signs of
melatonin is recognized to play an important role in skin bone metastases, and PTHrP immunoreactivity was detected
pigmentation, acting as a lightening agent (8, 67, 68). in melanoma cells on autopsy specimens but not in a biopsy

TABLE 2. Selected hormones and neurotransmitters produced in the skin

Compartment Hormones and neurotransmitter repertoire


Epidermis Vitamin D, PTHrP, androgens, T3, L-DOPA, catecholamines, acetylcholine, serotonin,
glutamate, aspartate, CRH, urocortin, ␣-, ␤-, ␥-MSH, ACTH, ␤-endorphin, enkephalins, TRH
Dermis and adnexal structures Vitamin D, PTHrP, estrogens, androgens, L-DOPA, serotonin, glutamate, aspartate, CRH,
urocortin, ␣-, ␤-, ␥-MSH, ACTH, ␤-endorphin, enkephalins, GH, histamine catecholamines,a
acetylcholinea
a
In the dermis, catecholamines and acetylcholine originate predominantly from cutaneous nerve endings.

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466 SLOMINSKI AND WORTSMAN Vol. 21, No. 5

TABLE 3. Selected neuropeptides generated in the skin

Source Neuropeptide
Resident and circulating skin cells Gastrin-releasing peptide, somatostatin, NPY, atrial natriuretic peptide, PHM/PHI, galanin,
neurokinins, substance P, neurotensin, CGRP, VIP, bradikinin, cholecystokinin, endothelins,
CRH, urocortin, ␣-, ␤-, ␥-MSH, ACTH, ␤-endorphin, enkephalins
Nerve endings Substance P, neurokinins, neurotensin, CGRP, VIP, somatostatin, NPY, atrial natriuretic
peptide, gastrin-releasing peptide PHM/PHI, bradikinin, galanin, cholecystokinin,
endothelins, ␣-, ␥-MSH, ␤-endorphin, CRH, urocortin, dynorphin, enkephalins

specimen of the melanoma obtained before onset of hyper- a. Human skin. The POMC peptides ACTH, ␣-MSH, and
calcemia (222). ␤-MSH and ␤-endorphin peptides have been detected by
immunocytochemistry in normal and pathological melano-
cytes, keratinocytes, Langerhans cells, and mononuclear der-
B. Hypothalamic and pituitary hormones
mal inflammatory cells (5, 17, 226, 227). Studies with RP-
1. CRH and related urocortin peptide. The skin is one of the HPLC and Western blotting in cultured human melanocytes
organs producing all the peptides hormones that are central and keratinocytes showed multiple forms of those peptides
components of the HPA, the main mediator of the systemic such as ACTH 1–10, acetyl-ACTH 1–10, ACTH 1–17, ACTH
response to stress (5, 6, 9, 16 –19, 25, 28, 36, 56). Among the 1–39, desacetyl-␣-MSH, ␣-MSH, and ␤-endorphin (5, 17,
hormones involved in this classic neuroendocrine pathway 228 –230). Human dermal endothelial cells and fibroblasts
are hypothalamic CRH and, more recently, the related pep- did not only produce, but also released, ␣-MSH and ACTH
tide urocortin (18, 19). In the skin, CRH gene expression has immunoreactivity into the medium (17, 64, 82, 108, 231). The
been detected in cultured human keratinocytes and mela- other POMC peptide, ␤-MSH, was detected by immunocy-
nocytes with actual production of the peptide, as shown by tochemistry in human skin in epidermal and follicular ker-
RIA and RP-HPLC; furthermore, the CRH antigen has been atinocytes, malignant keratinocytes, melanoma cells, and
localized in situ to epidermis, hair follicle, nerve bundles, and dermal inflammatory mononuclear cells (5). ␥3-MSH has
dermal blood vessels (18, 42– 44, 46, 49). In mouse skin, which also been detected in keratinocytes, melanoma cells, neutro-
does not express the CRH gene, high concentrations of CRH phils, and in nerve endings (5, 232).
have been detected by RIA, and chemical identification of
b. Rodent skin. ACTH, ␣-MSH, and ␤-MSH antigens were
CRH was documented by RP-HPLC analysis (44, 46). Since
the CRH immunoreactivity was localized to epidermal and detected in epidermal and follicular keratinocytes of mouse
follicular keratinocytes and in nerve bundles (43, 44), it was skin (5, 17, 83), and ACTH and ␣-MSH were also detected in
postulated that CRH is imported to the mouse skin by cu- nerve bundles and smooth muscle; ␤-endorphin has been
taneous nerve endings (43, 44, 46); alternatively, mouse skin identified only in the sebaceous glands (5, 83). Cultured
could express a related gene, with high homology to CRH murine and hamster melanoma cells expressed the ACTH,
(46). ␣-MSH, ␤-endorphin, and ␥3-MSH antigens (5, 16).
We recently observed expression of the urocortin gene in As regards the POMC gene expression, the transcription
mouse skin and also detected the actual urocortin peptide of shorter and longer POMC mRNA forms has been iden-
(19). Urocortin tissue levels were highest in telogen skin and tified in epidermal and dermal cells (5, 17). This pattern was
decreased progressively during hair cycle to the lowest level accompanied by translation of a 30-kDa POMC precursor
in late anagen (19). This pattern is opposite to the hair cycle- and its subsequent processing to ACTH, ␣-MSH, ␤-MSH,
associated production of CRH as determined in the same ␤-endorphin, and ␥3-MSH peptides (5, 17). Detection of the
model (44). Expression of the urocortin gene has also been processing enzymes PC1 and PC2 convertases in human and
documented in whole human skin, human keratinocytes, rodent skin indicates that processing of POMC in skin is
human melanocytes, and in hamster melanoma cells (19). similar to that in the hypothalamus and pituitary (17, 108,
Similar to CRH, expression of urocortin peptide was detected 232a). It must be noted that one group has reported only 80%
in situ in the epidermis, hair follicle, sweat glands, melano- homology between the human cutaneous POMC mRNA and
cytic nevi, smooth muscle, and wall of blood vessels (19). The its pituitary counterpart (233); however, subsequent analysis
reported expression of CRH and urocortin in lymphocytes of the reported sequence by others showed contamination
(224, 225) strongly suggests that cells of the skin immune with murine pituitary POMC cDNA (234).
system may also contribute to the cutaneous pool of those Therefore, the information above is convincing evidence of
peptides. Therefore, the hormone products that initiate HPA POMC peptide production in the skin and its processing to
activation at the central level are also readily available in the ␣-MSH, ACTH, and ␤-endorphin-related peptides. Defini-
skin. tion of local production of other products of POMC process-
ing will require additional research.
2. POMC. There is a large body of data documenting ex-
pression of POMC gene in whole human and rodent skin and 3. Other pituitary hormones. Studies with in vitro systems have
in cultured skin cells that include keratinocytes, melanocytes, shown that human dermal fibroblasts express PRL mRNA
dermal fibroblasts, and endothelial cells, Langerhans cells, 150 kb longer than the pituitary form (235). However, the
monocytes/macrophages, T lymphocytes, and leukocytes fibroblasts synthesized and secreted PRL peptide, immuno-
(5, 16, 17, 64, 83). logically and electrophoretically identical to pituitary PRL

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October, 2000 NEUROENDOCRINOLOGY OF THE SKIN 467

(235). The data are also consistent with earlier observations migrate, within dense core vesicles through retrograde ax-
of PRL production by normal human connective tissue (236), onal transport, to nerve endings in the skin (34). The skin
and with detection of PRL immunoreactivity in sweat glands concentration of neuropeptides varies by anatomical site,
(237, 238). Expression of the human GH gene has also been reflecting, probably, regional differences in innervation (4,
detected by RT-PCR in cultured dermal fibroblasts (239); 33, 253). It is generally accepted that afferent or efferent
human endothelial cells express the PRL gene (240); and nerves are the main source for the cutaneous neuropeptides
human immune cells produce both PRL and GH (25, 241– listed above.
243). Our most recent studies indicate restricted expression An additional source of cutaneous neuropeptides is their
of GH gene in the dermal compartment, that failed to detect synthesis and secretion by resident and circulating skin cells,
production of PRL mRNA in whole human skin (243a). present in inflamed or even normal skin (4, 7, 24, 25, 27, 28,
Therefore, actual GH and PRL production by the main cu- 38, 110, 111, 115, 254, 255). For example, Merkel cells express
taneous cell compartments has yet to be determined. antigens that are recognized by antibodies against CGRP, SP,
NKA, VIP, PHI, NPY, SOM, and galanin (38, 111, 112, 255).
Likewise, Langerhans cells express CGRP, SP, GRP, VIP,
C. Neuropeptides and neurotrophins SOM, and NKA antigens (110, 254). It remains to be tested
1. Enkephalins. Met-enkephalins (Met-E) and leu-enkephalins whether expression of those antigens is connected to actual
(Leu-E), which are products of the larger protein precursor transcription and translation of the corresponding genes.
proenkephalin A (PEA) (36, 68), are also produced by mam- Several immunocytochemical studies have reported the
malian skin (88, 244 –249). Met-E immunoreactivity has been presence of VIP, SOM, SP, CGRP, NPY, and NKA in dermal
detected in normal human skin and is increased in areas and epidermal immune cells from skin affected with psori-
affected by psoriasis (88, 244, 245). The corresponding anti- asis, urticaria pigmentosa, allergic dermatitis, and, in some
gen is located in epidermal keratinocytes and in inflamma- cases, uninvolved normal skin (4, 7, 38, 110, 111, 254, 255).
tory infiltrate components such as T lymphocytes, macro- NPY has been additionally detected in epidermal and fol-
phages, and leukocytes. Met-E has been also detected in the licular keratinocytes of normal skin and SOM in basal epi-
keratinocytes of basal, spinous, and granular layers of hu- dermal keratinocytes of atopic dermatitis skin (38, 133, 254).
man and murine epidermis (88, 245, 250). The detection of Thus, skin cells definitively can produce neuropeptides;
PEA mRNA in lesional psoriatic skin further supports local however, the conditions necessary for such production and
production of the Met-E peptide (244). The cellular source the precise identity of the producing cells remain to be de-
expressing PEA could be mesenchymal dermal cells (248, fined.
249) or immune cells including mast cells (24, 25), since
regulated PEA mRNA expression and production of final 3. Neurotrophins. The skin can produce the neurotrophins
enkephalin peptides has been detected in rodent skin mes- NGF, NT-3, NT-4, and brain-derived neurotrophic factor
enchymal cells (249), and circulating immune cells express (BDNF) (7, 123–125, 128 –130, 256 –258). NGF is synthesized
the PEA gene (251). The Met-E peptide has been also detected and secreted by keratinocytes, Merkel cells, and dermal fi-
in epidermal Merkel cells and Langerhans cells (246, 247). broblasts and mast cells (7, 123, 128, 256 –258). In human skin,
Upon further review of the data, it appears that cell type and production of NT3 has been detected in dermal fibroblasts
conditions necessary for expression of the PEA gene remain (124), whereas in the mouse it is more widely expressed since
to be determined. Similar research is needed to determine the NT3 is found in epidermal and follicular keratinocytes of
cellular source of pro-dynorphin-related peptides, the pres- developing skin, and in adult animals it is detected in ker-
ence of which has been reported in mammalian skin (252). atinocytes of hair follicle and DP fibroblasts (128 –130). Hair
follicle keratinocytes can synthesize NT4 and NGF (128 –130),
2. Nonopioid neuropeptides. Mammalian skin expresses a va- and dermal Schwann cells can synthesize NGF, NT-3, and
riety of neuropeptides that include tachykinins SP and NKA, NT-4. Locally produced neurotensin can induce mast cell
CGRP, VIP, NPY, somatostatin (SOM), galanin, atrial natri- degranulation (203). It may be speculated that the pleomor-
uretic peptide (ANP), peptide histidine methionine/peptide phism of neurotrophin cutaneous expression could be re-
histidine-isoleucinamide (PHM/PHI), bradykinin, cholecys- lated to their significance in regeneration, a functional ca-
tokinin (CKK), and gastrin-releasing peptide (GRP) (4, 7, 33, pability vital for the maintenance of homeostasis.
34, 38, 108 –114). In normal human skin, the most abundant
of these peptides are SP, CGRP, VIP, and NPY, although D. Neurotransmitters/neurohormones
detectable but lower levels of NKA, SOM, and ANP are also
present. Neuropeptides are synthesized by nerve cells and 1. Acetylcholine. Cultured human keratinocytes can synthe-
released predominantly by unmyelinated afferent C fibers size, secrete, and degrade acetylcholine (180, 181, 259).
characterized as C-polymodal nociceptors (C-PNN) and by Keratinocyte acetylcholine is synthesized by choline acetyl-
small myelinated A␦-fibers (33, 34, 38, 108). To a lesser extent, transferase from acetyl coenzyme A and choline; in turn,
autonomic efferent nerves also release the neuropeptides (4, acetylcholine is hydrolyzed by acetylcholinesterase to acetate
33, 34). In general, nerves penetrating into the epidermis and choline. Activities of both enzymes, choline acetyltrans-
contain SP, NKA, and CGRP, whereas those innervating ferase and acetylcholinenesterase, have been detected and
dermal structures contain SP, CGRP, VIP, and NKA (33). The characterized in homogenates of cultured keratinocytes.
neuropeptides are synthesized in dorsal root ganglia, where Immunolocalization studies have shown that choline acetyl-
they are processed and sorted in the Golgi network and then transferase is consistently present in all layers of the human

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468 SLOMINSKI AND WORTSMAN Vol. 21, No. 5

epidermis, while acetylcholinesterase is restricted to basal formation would occur in the epidermal keratinocytes
keratinocytes (180, 181, 259). Acetylcholinesterase activity through the action of type 2 deiodination pathway (280, 281),
has been also detected in situ in epidermal melanocytes with efficiency inversely related to the serum T4 (12). The
(260). In addition to local synthesis, acetylcholine is also human epidermis is also the site of T3 deiodination to 3,3⬘-
released by cholinergic nerve endings supplying dermal diiodothyronine (12). More recent data suggest, however,
structures (34). that at least rodent skin expresses only deiodinase type 3,
which catalyzes the 5-deiodination of thyroid hormones
2. Catecholamines. The human epidermis has the capability (283–285). Since the cutaneous expression of three deiodi-
to synthesize the catecholamines dopamine, norepineph- nases in rodent skin changes during embryonal develop-
rine, and epinephrine (21, 22, 187, 261–263), which is con- ment, this area needs to be reexamined with modern meth-
sistent with previous findings of phenylethanolamine-N- ods, as it applies to human skin (284, 285).
methyl transferase immunoreactivity in human epidermal
keratinocytes (264). The synthetic activity of cutaneous
F. Sex steroid hormones
catecholamines resides predominantly in keratinocytes
that express biopterin-dependent tyrosine hydroxylase The skin can transform the steroids dehydroepiandros-
and phenylethanolamine-N-methyl transferase (21, 187, terone (DHEA) and its sulfate (DHEA-S) into active andro-
261, 262). Catecholamine production takes place in human gens and estrogens (4, 160, 286 –288). Specifically, enzymatic
and rodent melanoma cells (265, 266), which suggests that activity corresponding to 3␤-hydroxysteroid dehydroge-
normal melanocytes may also produce catecholamines nase/⌬5–⌬4 isomerase (3␤-HSD) has been localized to the
(267). Catecholamines can be inactivated directly in the sebaceous glands and, to a lesser degree, in hair follicles,
epidermis by the enzymes monoamine oxidase (MAO) and epidermis, and eccrine glands, while 17␤-hydroxysteroid de-
by catechol-methyl transferase, the enzyme already char- hydrogenase (17␤-HSD) has been localized to follicular and
acterized in keratinocytes and melanocytes (187, 268, 269). epidermal keratinocytes (287–291). 3␤-HSD converts DHEA
l-Tyrosine, a precursor for both catecholamines and for into 4-androstenedione, and 5-androstene-3␤,17␤-diol into
melanin, is also synthesized in human keratinocytes and me- testosterone, while 17␤-HSD converts DHEA into 5-andro-
lanocytes from l-phenylalanine by phenylalanine hydroxylase stene-3␤,17␤-diol, 4-androstenedione into testosterone, and
(20, 21, 187, 262, 270). Moreover, phenylalanine hydroxylase androstanedione into DHT (4, 36, 160). Testosterone is also
and tyrosine hydroxylase activities are dependent on the co- converted into DHT through the action of a 5␣-reductase,
factor 6BH4, which is also synthesized and recycled by human detected in dermal and dermal papilla fibroblasts, follicular
keratinocytes and melanocytes (21, 22, 187, 261). Lymphocytes and epidermal keratinocytes, and sebaceous and apocrine
may also represent an additional source of catecholamines glands (4, 160, 164, 286, 289 –297). There are two isozymic
(271). It has been proposed that l-tyrosine and its hydroxylation forms of the 5␣-reductase, but the skin expresses predomi-
product l-DOPA would have hormone- and neurotransmitter- nantly the type I in a highly specific cellular and regional
like roles (23, 214, 272), with melanocytes being the main site of distribution (290 –296). Nevertheless, cutaneous expression
cutaneous l-DOPA production through the tyrosine hydroxy- of 5␣-reductase type 2 has been also reported, but at much
lase activity of tyrosinase (8, 273). l-DOPA produced by me- lower levels; this form has been immunodetected in hair
lanocytes can, in fact, be released into the extracellular envi- follicles of human scalp (295, 296). The skin immune system
ronment. As for norepinephrine, an important cutaneous can also convert DHEA into 5-androstene-3␤,17␤-diol and
source is its dermal release from adrenergic nerve fibers (4, 33, into 5-androstene-3␤,7␤,17␤-triol. Cutaneous conversion of
34). testosterone into estradiol is mediated by an aromatase ex-
pressed in dermal fibroblasts and adipocytes, but not in
3. Other neurohormones. Serotonin may be also synthesized in keratinocytes (4). However, in keratinocytes 17␤-HSD can
the mammalian skin, since rodent mast cells can synthesize transform 17␤-estradiol into estrone or estrone into 17␤-
serotonin, although this property is not shared by human estradiol (286).
mast cells (7, 27, 115, 195). Serotonin has also been detected
in Merkel cells and human melanocytes and melanoma cells
(266, 274, 275). In rodent skin serotonin can be transformed G. Other steroid hormones
into N-acetylserotonin (NAS), and the responsible enzyme The presence of 17␤-HSD indicates that skin can dehy-
arylalkylamine N-acetyltransferase, together with its gene, drogenate pregnenolone into progesterone, although the re-
are correspondingly expressed (196, 276, 277). In hamster action does not proceed in cultured keratinocytes (286). The
skin NAS can be further metabolized to melatonin and 5- skin expresses genes for cytochromes P450SCC, P450c17, and
methoxytryptamine (278). Finally, the neurotransmitters glu- P450c21 (66). Immunocytochemistry localization of the an-
tamate and aspartate have been detected by immunocyto- tigens for cytochrome P450SCC and P450C17 showed the
chemistry in epidermal keratinocytes and in dermal and former in epidermal keratinocytes and eccrine glands and the
epidermal dendritic immunocytes (279). latter in epidermal and follicular keratinocytes, and in se-
baceous and eccrine glands (102). These findings, together
E. Thyroid hormones with the expression of the ACTH and of the MC2-R gene,
suggest that the skin could potentially synthesize glucocor-
Human skin may be an extrathyroid site of conversion of ticoids (66). In fact, early studies have shown that whole
T4 into the more active T3 (12, 280 –282). This metabolic trans- human skin can metabolize progesterone (PROG) (4), while

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October, 2000 NEUROENDOCRINOLOGY OF THE SKIN 469

human keratinocytes can transform DOC into 5␣-dihydro- tion, whereas ACTH modifies hair growth (5, 16, 35, 61, 83,
DOC (286). We have recently reported that skin-derived ma- 86). Cutaneously produced CRH and urocortin affect epi-
lignant melanocytes can indeed metabolize exogenous dermal proliferation of keratinocytes and melanocytes (18,
PROG to DOC, corticosterone, and 18OHDOC, and that it 19, 46, 51), and in the dermis these peptides can modify local
can also metabolize DOC to corticosterone and 18OHDOC immune responses and act as vasodilators and mast cell
(Fig. 1) (298). A more physiological preparation, whole skin segregators (40, 48, 56 – 60, 203).
from the rat, can transform PROG into DOC and metabolize There is important neural representation in the skin, and
DOC to corticosterone-like and to 11-dehydrocorticosterone- one of its components is the epidermal cholinergic system
like molecular species (Fig. 2) (299). (20). Its neurotransmitter, acetylcholine, is produced by the
keratinocytes in which, through interactions with muscarinic
and nicotinic receptors expressed predominantly in the basal
or suprabasal epidermal layers, keratinocyte proliferation,
V. Molecular and Structural Basis for the
migration, and differentiation are regulated (20, 181, 259).
Organizational Integration of Neuroendocrine
Acetylcholine availability is determined by the local concen-
Elements of the Skin
tration of acetylcholinesterase, which is highest in the basal
It is apparent from the massive amount of data summa- layer and decreases gradually along the vertical axis to reach
rized in this work that the skin function extends beyond that its lowest levels below the stratum corneum (20, 181). The
of static barrier organ. Thus, in addition to separating the adrenergic system, represented by the catecholamines pro-
external environment from internal homeostasis, the skin duced by keratinocytes, interacts with adrenergic receptors
also exerts important endocrine and exocrine activities (cf. expressed on the same cells to regulate their phenotype (21,
Fig. 3). The well characterized exocrine function is performed 187, 300). The local production of the nonessential amino acid
by the adnexal structures that comprise eccrine, apocrine, l-tyrosine from l-phenylalanine by melanocytes and kera-
and sebaceous glands and hair follicles. These are important tinocytes ensures its availability for catecholamine synthesis
in strengthening the epidermal barrier, in thermoregulation, and melanogenesis in the epidermal unit, independent of
and in the defense against microorganisms (3, 4, 7, 11). For- systemic supply (21, 22, 261). Both l-DOPA, a product of
mation of the hair shaft together with the secretions of ec- local l-tyrosine hydroxylation, and catecholamines can po-
crine, apocrine, and sebaceous glands also plays an impor- tentially modify cutaneous immune responses (215, 271).
tant role in social communication. Furthermore, at least in As regards sex hormones actions, testosterone by itself, or
furry animals, the skin plays an important role in behavioral after conversion to DHT in keratinocytes and dermal fibro-
regulation, ascribed to the exocrine activity of the specialized blasts modifies hair growth and sebaceous glands function
and nonspecialized sebaceous glands that produce and se- (4, 163, 164). Dermally produced estradiol (4) can affect func-
crete odorants and pheromones (35). tion of adnexal structures and the wound healing process
As regards the newly recognized endocrine function of the (172, 173).
skin, this is performed by cells compartmentally arranged As discussed in the section on the vitamin D receptor, the
into endocrine units (Fig. 4). These units are composed of active vitamin D3 metabolite 1,25-(OH)2D3 inhibits keratin-
cells of epithelial, neural crest, mesenchymal, and bone mar- ocytes proliferation and stimulates their differentiation via
row origin that form the epidermal, dermal, and adnexal interaction with the VDR (13, 14). Evidence for the epidermal
structures (cf. Figure 3). As listed in Tables 1 and 2, these conversion of vitamin D into 1,25-(OH) 2D3 (301) would
cutaneous cells and adnexal structures can concomitantly further support local (auto- and paracrine) mechanisms of
produce hormones and express the corresponding receptors action. PTHrP produced in the epidermis and hair follicle has
(see Section III), indicating that the predominant mechanisms a similar effect on keratinocytes through interaction with a
of interaction within the different cutaneous compartments receptor different from the classic class 1 PTH/PTHrP re-
are auto- and paracrine in nature. For example, the common ceptor (15, 302). Both vitamin 1,25-(OH) 2D3 and PTHrP can
skin stressor, UV radiation, stimulates epidermal production affect hair growth (13–15, 302).
and secretion of the POMC-derived MSH and ACTH pep- Notwithstanding their overwhelming local action, hor-
tides. In turn, these peptides interact with MC receptors on mones produced in the skin can also enter superficial and
melanocytes, keratinocytes, and Langerhans cells (LC) to deep vascular dermal plexuses, or vessels supplying adnexal
modify their functional activity and increase cutaneous mel- structures, with long distance effects. Such a true endocrine
anin pigmentation (5, 9, 17, 64) and also generate local an- role is most apparent in the case of hormones and cytokines
tiinflammatory and immunosuppressive effects (17, 64, 108). produced in the dermis that have rather free access, by dif-
Immunosuppression, mediated predominantly by ␣-MSH, is fusion to local capillary vessels. Limiting factors for this
expressed as functional antagonism to IL-1, down-regulation diffusion are the distance between production site and vas-
of accessory molecules expression on antigen presenting culature, adhesiveness to the extracellular matrix, and local
cells, and stimulation of IL-10 secretion (17, 64, 82, 108). At rate of degradation. In contrast, epidermally produced hor-
the dermal level these immunosuppressive effects include mones and cytokines must penetrate the basement mem-
modulation of local cytokine production, and inhibition of brane (BM) before traversing the extracellular matrix (EM) of
endothelial cells expression of adhesion molecules necessary the papillary dermis; therefore, the permeability barrier and
for inflammatory cells transmigration through the capillary the adhesiveness to the BM and EM limit their access to the
network (7, 17, 64, 82, 108). Dermally produced ␣-MSH and most superficial capillary vessels. An example of the relative
ACTH modify hair pigmentation and sebaceous gland func- restriction posed by the dermal-epidermal junction is the

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470 SLOMINSKI AND WORTSMAN Vol. 21, No. 5

FIG. 1. Metabolism of progesterone to DOC, corticosterone, and 18OHDOC in malignant melanocytes. A, TLC separation of 14C-progesterone
metabolites produced by melanoma cells. B, RP-HPLC identification of 3H-18OHDOC as a metabolite of 3H-DOC. Upper panel, UV detection
of 18OHDOC standard; lower panel, radioactivity in eluted fractions with arrow indicating 3H-18OHDOC peak. C, Enzyme-linked immu-
nosorbent assay (ELISA) identification of corticosterone (B) in RP-HPLC-separated fractions. Upper panel, UV detection of corticosterone (B)
standard; lower panel, immunoreactive corticosterone (arrow) in media from human melanoma cells incubated with progesterone. Control
represents media from cells cultured without progesterone added. DOC, 11-Deoxycorticosterone; B, corticosterone; Aldo, aldosterone; 11-
dehydro-B, 11-dehydrocorticosterone; 18ODOC, 18-hydroxycorticosterone. [Reproduced with permission from A. Slominski et al.: FEBS Lett
445:364 –366, 1999 (298). Experimental conditions are detailed in Ref. 298.]

rarity of patients showing systemic effect (hypercalcemia) activity of distant organs, providing evidence for endocrine
from cutaneous PTHrP, a hormone produced abundantly in effects by factors produced in the epidermis. Urocanic acid
the epidermis (15, 302). Still, epidermally produced vitamin produced in the stratum corneum of the epidermis can also
D (14), urocanic acid (303, 304), and, perhaps, PTHrP do enter enter the systemic circulation and have immunosuppressive
the systemic circulation and are able to modify the functional effects (4, 123, 303, 304). As mentioned above, epidermal

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October, 2000 NEUROENDOCRINOLOGY OF THE SKIN 471

FIG. 2. Active steroidogenesis in normal rat skin. Both panels show TLC separation of steroid products. The right lanes marked 14C-PROG (A)
or 14C-DOC (B) show radioactive steroid intermediates generated in rat skin. The left lanes marked controls represent nonenzymatic trans-
formation of 14C-PROG (A) or 14C-DOC (B) incubated in culture media only. Experimental conditions are detailed in Ref. 299. PROG,
Progesterone; DOC, 11-deoxycorticosterone; B, corticosterone; Aldo, aldosterone; A, 11-dehydrocorticosterone; 18OHB, 18-hydroxycorticoste-
rone. [Reproduced with permission from: A. Slominski et al.: Biochim Biophys Acta 1474:1– 4, 2000 (299). © Elsevier Science.]

PTHrP may play predominantly para- or autocrine roles (15, represents therefore a high-speed and extremely specific con-
141). It could, however, have a distant effect after release by nection for the transfer of information, sensed externally or
pathological conditions (skin cancer) (222, 223). internally, to specific target cells. Target cell activation may
Cutaneous neuroendocrine elements are therefore tightly then be mediated by neuropeptides (cf. Table 3 and Section
organized and arranged into epidermal and dermal endo- IV.C) synthesized and released predominantly by the un-
crine units, as determined by the physical separation be- myelinated C fibers described as C-polymodal nociceptors
tween those compartments (Figs. 4 and 5). These units, which (C-PNN), or by myelinated A␦-fibers (33, 34, 38). There are
become fully expressed in a field-restricted stress-dependent specific roles for each of the different neuropeptides released
manner, have broad bidirectional communications. This is by afferent nerve endings in the functional regulation of
accomplished through soluble factors able to penetrate the epidermal barrier properties, skin immune activity, vascular
basement membrane and, also, through sensory nerve end- activity, hair growth, and adnexal functions. Those topics, as
ings connecting epidermis and dermal structures (Figs. 4 and well as their mechanism of action, have been discussed in
5). Sensory nerve fibers provide anterograde or retrograde comprehensive reviews on the subject (5, 7, 33, 34, 38, 56,
transmission of impulses through axon reflexes with release 110 –112, 128, 203). It is apparent from neuroimmunocyto-
of neuropeptides at epidermal or dermal nerve endings (33, chemistry studies that nerve subpopulations containing dif-
34, 38). The latter intracutaneous communication mechanism ferent neuropeptides, such as SP, NKA, CGRP, VIP, SOM,

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472 SLOMINSKI AND WORTSMAN Vol. 21, No. 5

FIG. 3. Localization of the cellular com-


ponents of the exocrine and endocrine
skin units. The epidermis is repre-
sented by the upper layer, separated
from the dermis by the basement mem-
brane. The listed cell types have the
capability to produce hormones, neural
mediators, and cytokines; they also ex-
press the corresponding receptors indi-
cating auto- and paracrine mechanisms
of action.

NPY, PHM, enkephalins, CRH, and ␥- and ␣-MSH, do enter dermis; however, this hypothesis still requires experimental
cutaneous structures. The presence of this neural network investigation.
with fibers penetrating all the vital layers of the epidermis The bidirectional interaction between skin elements and
and branching into dermal structures, adnexa, Merkel cells, local neural network is perhaps best illustrated by the
epidermal Langerhans cells, melanocytes, and dermal mast changes in murine skin during the hair cycle, which are
cells provides, therefore, the support for a dual role for those dependent on appropriate dermal and adnexal innervation
cells, as effectors and regulators (33, 34, 38, 110, 114, 115, 118, (128, 300, 311). In this process, the hair cycle-associated tissue
119, 128, 203, 300, 305–313). Within this local branching neu- remodeling is accompanied by a tightly regulated sprouting
ral network, disturbances of local homeostasis expressed as and regression of specific afferent and efferent nerve fibers
production of chemical mediators can be sensed in a specific that form a neural and neurotransmitter network. Its cuta-
manner and transmitted to local subunits to counteract nox- neous expression is highly specific and tightly determined by
ious stimuli or protect against further damage. The neural the actual phase of the hair cycle (128, 300, 311).
branches can be also activated directly by neurohormones The epidermal and dermal endocrine units with their bi-
and bioactive peptides produced locally, such as histamine, directional communication pathways, which proceed via sol-
eicosanoids, or NO (33, 34, 38, 112, 203, 312, 314); or, by uble mediators or via antidromic axon reflexes through the
physicochemical agents such as changes in pH, cation, and nerve branches that link both compartments, combine to
free radical concentration (cf. Ref. 34). Indirect neural mod- form the skin neuroendocrine organization (Fig. 5). In gen-
ulation may be provided by the cytokine networks that mod- eral, this neuroendocrine organization functions to coordi-
ify the chemical environment surrounding the nerve end- nate the epidermal and dermal changes necessary for rein-
ings. As compared with this neural mechanism, humoral forcing the physical barrier and maintaining its structural
communication, dependent on local diffusion, results in a integrity. To implement these objectives, it modulates sen-
much slower response. sory reception, melanin pigment production and distribu-
The special role of autonomic nerves in the cutaneous tion, activity of the local immune system, vascular functions,
neuroendocrine organization is limited by the predominant thermoregulation, exocrine secretion, and metabolic trans-
dermal ending of their fibers. Thus, they can only regulate formation of prohormones or hormones into other molecules
function in the dermal endocrine unit although neurotrans- of different biological activity.
mitters released in the proximity of the basement membrane The skin neuroendocrine system is thus continuously
could potentially diffuse into the epidermal compartment. It sensing environmental components and, when activation
is also possible that autonomic nerves could enter the epi- threshold levels are reached, a reaction is triggered with

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October, 2000 NEUROENDOCRINOLOGY OF THE SKIN 473

FIG. 4. Diagram demonstrating the proposed flow of information


between dermal and epidermal endocrine units and their systemic FIG. 5. Organization and function of the skin neuroendocrine system.
connections. For functional purposes, cells with endocrine capability The epidermal and dermal endocrine units modulate functional ac-
become activated in response to environmental stimuli in a stress- tivity of epidermal and dermal compartments. Endocrine units coor-
dependent manner, organized according to anatomic compartment of dinate their actions by humoral signals (central arrows) and/or by the
residence. They communicate by humoral signals (central arrows) and local neural network (connecting arrow on the left).
sensory nerve endings (arrows on the left). The efferent neural
regulation is provided by the autonomic nerves (right), and also by
sensory nerves (left) via antidromic conduction. Cytokines may have similar action on the regulation of
adrenal gland function (28, 317). Intermediates of melano-
production of specific biological factors. Some of these fac- genesis l-DOPA and products of its metabolism in the me-
tors may be released to the extracellular compartment to lanocytes might also have systemic effects when, under
activate sensory nerve endings, directly enter the circulation, pathological conditions, they are released into the circulation
or activate circulating immune cells. The sum of these actions (10, 23, 318).
sets the optimal mode for dealing with deleterious environ- Many epidermally or dermally derived molecules are in-
mental changes (Fig. 6). Humoral signals that could directly capable of migrating because of insignificant concentration
enter the circulation include cytokines and hormones and in the vicinity of blood vessels; however, a systemic effect is
vitamin D3. The latter represents a marker for a cutaneous still theoretically possible. Thus, direct stimulation of dermal,
action in response to an environmental component (UV-B), adnexal, or subcutaneous cellular components could second-
which results in well defined systemic effects on calcium arily result in the production of biological mediators with
homeostasis (14). An analogous example in amphibians is the definite systemic effects. An example of this amplification
skin regulation of pituitary function through TRH and skin mechanism is represented by the cytokines IL-1 and TNF␣,
peptide tyrosine-tyrosine (SPPY) (315, 316). Environmental which can stimulate leptin production by adipose tissue in
factor(s) determine concentrations of TRH and SPPY in frog the deep dermis and/or subcutis (319, 320). In this manner,
skin, which are higher than in any neuroendocrine organ; small amounts of cutaneous cytokines could affect feeding
skin TRH reaches the pituitary to stimulate production and behavior and energy balance (319). Another example is the
release of PRL and ␣-MSH, while SPPY inhibits production activation of skin immune cells that can enter the circulation
of ␣-MSH (315, 316). In mammals, there are other local and have distant immunological or regulatory effect (7, 27).
hormonal factors that could potentially enter systemic cir- Similar to the humoral model of communication in the
culation after UV radiation exposure or in pathological con- cutaneous endocrine system, with potential cytokine-medi-
ditions. Among those are POMC-derived ␣-MSH and ␤- ated stimulation of the HPA axis, the cutaneous neural sig-
endorphin (5, 9, 108, 230), met-enkephalin (245), PTHrP (15, naling system could also activate central nervous system
302), or DHT, estradiol, and T3 (4, 11, 12). Skin cytokines can pathways. The latter connections have the advantages of
also directly affect the functional activity of distant immune being more rapid with higher specificity (Fig. 6). Thus,
and nonimmune organs (7, 11, 17, 27, 108), whereas circu- changes in the skin physicochemical environment generated
lating cytokines are known to affect hypothalamo-pituitary by physical, chemical, or biological trauma, UV radiation, or
axis function (24 –28). Thus, IL-1, IL-6, interferons, and TNF␣ local disease processes could be sensed by afferent nerve
can access brain and pituitary to up-regulate production and ending, and thence transmitted via the spinal cord to the
release of selected hypothalamic and pituitary hormones. brain. However, before the information is sent to the brain,

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474 SLOMINSKI AND WORTSMAN Vol. 21, No. 5

the spinal cord to other organs without ever reaching the


higher centers. To summarize, the skin can generate rapid
(neural) or slow (humoral) moving signals to induce re-
sponses at the general or systemic level or at the organ-
specific level. These responses are designed to counteract the
damaging effect of environmental insults or to adjust the
homeostatic system to the optimal mode that would buffer
environmental noxious agents most efficiently.

VI. Regulation of Cutaneous Neuroendocrine System


There are number of environmental and intrinsic factors
that regulate the cutaneous neuroendocrine system activity
level. The most prominent environmental factor affecting the
skin is solar radiation, particularly within the UVA and UVB
wavelengths. Temperature, humidity, and concentrations of
chemical and biological agents represent other factors. Some
internal factors affecting the skin neuroendocrine system are
changes in the physicochemical microenvironment or in bi-
ological modifiers; these may be generated in reaction to
environmental signals or result from local cyclic biological
rhythm associated with hair cycling, or from local or general
disease processes. Of the endocrine factors produced by the
skin the most important is vitamin D, which is not only a
regulator of the calcium metabolism but has other systemic
effects (13, 14, 145). For example, epidemiological evidence
suggests that sunlight deprivation with associated reduction
in the circulating levels of vitamin D3 derivatives may result
in increased incidence of the carcinomas of breast, colon, and
prostate (145).

A. Solar radiation

FIG. 6. Systemic effects of skin neuroendocrine system products. In UV light is a form of electromagnetic energy that includes
response to noxious stimuli, the skin endocrine system mounts a the wavelength between 100 to 400 nm of the solar spectrum.
progressive, intensity-dependent, highly coordinated response. In the Although it includes vacuum UV, UVC, UVB, and UVA, only
case of high-magnitude stimuli, the generated signals travel through
humoral or neural pathways to reach the central nervous system, the 290 – 400 nm wavelengths that comprise UVA and UVB
immune system, and other organs. reach the surface of the earth, because of the partial absorp-
tion by atmosphere. UVB (290 –320 nm) interacts very effi-
it may be modulated by the local cutaneous neuroendocrine ciently with the skin, inducing sunburn and pigmentation (3,
units through the direct activation of nerve receptors by 4, 9). UVA (320 – 400 nm) has better penetration through the
neurohormones and neurotransmitters, or by neuropeptides atmosphere but lower efficiency in inducing erythema and
(cf. Tables 2 and 3), histamine, eicosanoids, NO, and other melanogenesis. It is classified as UVA1 (320 –340 nm) and
proinflammatory mediators (5, 7, 27, 33, 34, 108, 113, 203, UVA2 (340 – 400 nm), and it has been proposed that the
314). Alternatively, stress released cytokines and proinflam- photobiological mechanism of action for UVA1 is similar to
matory biological modifiers could affect signal type and neu- that of UVB; the effects of UVA2 would involve distinctive
ral sensor availability through indirect mechanisms, e.g., ac- oxygen-dependent photochemistry. The cutaneous effects of
tivation of other cells to produce and release factors UV radiation are dependent on the penetration and absorp-
activating afferent receptors. In this context, mast cells, me- tion of the particular wavelength. In human skin UVB is
lanocytes, Langerhans cells, and Merkel cells could be par- absorbed predominantly by stratum corneum and to a lesser
ticularly important because of their close contact with nerve degree by the epidermis. The very small fraction of UVB that
endings (33, 34, 110, 111, 119, 203, 305–308). Secondary reaches the dermis, however, has significant biological ef-
changes in hydrogen ions, cations, free radical and NO con- fects inducing immediate and delayed erythema (3, 4, 9).
centrations or eicosanoids produced by cytokine-activated Transmission of UVA through epidermis of white skin is
keratinocytes or immune cells could have similar effects on high, resulting in approximately 50% of energy reaching the
sensory nerve endings. In the visceral organs the cytokine dermis. UVA has only 1/1,000 of UVB biological activity, but
IL-1, IL-6, and TNF␣ signals can be potentially transmitted it also contributes to the cutaneous actions of solar radiation
through an indirect mechanism via the vagus nerve to the (3, 4, 9). Thus, it has a major effect in aging of the skin, it has
central nervous system (26, 28, 321). Lastly, upon leaving the a more limited role in the induction of skin cancer, and it does
skin, some afferent neural signals may also be relayed from not produce burning of the skin. In general, the biological

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October, 2000 NEUROENDOCRINOLOGY OF THE SKIN 475

responses to solar radiation are dependent on individual indirect through UV-induced activation of nonimmune cells
susceptibility determined by skin pigmentation, prior expo- in epidermis and dermis with release of cytokines and chem-
sure to UV radiation (decreases the threshold for subsequent ical mediators (7, 9, 17, 64, 82, 108, 114, 326 –333). Important
responses), region affected, radiation field size, and envi- in this regard is trans-urocanic acid (UCA) which, after ab-
ronmental conditions (3, 4, 9). There is, nevertheless, a high sorption of UVB, or to lesser degree of UVA energy, isomer-
degree of precision and predictability of the cutaneous re- izes into cis-UCA in the stratum corneum (303, 304). cis-UCA
sponse to UV, demonstrating that mechanisms have evolved acts as a potent local and systemic immunomodulator and
to transform some of the solar energy into a catalyst acti- immunosuppressor (7, 303, 304).
vating a recording system (9). Such a recording role could be Keratinocytes stimulated by UVR can produce and secrete
served by the local neuroendocrine system, whose activation the cytokines IL-1, IL-6, IL-8, IL-10, IL-12, IL-15, TNF␣, and
is designed to buffer or counteract the damaging effect of UV. macrophage inhibitory factor (MIF), eicosanoids, basic fibro-
blast growth factor (bFGF), IGF-I, transforming growth fac-
1. CRH-POMC system. UVB stimulates production of CRH tor (TGF-␣), and endothelins (7, 17, 108, 114, 326 –333). This
peptide in normal melanocytes without noticeable changes effect is rapid (within 1–3 h) and predominantly mediated by
in CRH mRNA levels, suggesting posttranscriptional regu- UVB, although UVA also stimulates IL-10 and, to a lesser
lation (322). UVR can stimulate/induce POMC gene expres- degree, IL-6 production. UVR also switches the local cyto-
sion in the skin in human and rodent normal and malignant kines and mediators release profile of nonepithelial compo-
keratinocytes and melanocytes maintained in cell culture (5, nents of epidermis and dermis including lymphocytes, mac-
9, 17, 64, 108, 230, 323). The stimulation of ACTH, ␣-MSH, rophages, mast cells, endothelial cells, and melanocytes. The
␤-LPH, and ␤-endorphin production and secretion in re- cytokines IL-1, IL-6, TNF␣, and MIF exert local activity,
sponse to UVB is dose dependent in normal and malignant which does not preclude systemic effects upon entering the
epidermal cells, and in dermal endothelial cells; POMC circulation.
mRNA production is correspondingly increased (17, 64, 108,
323). UVA can also stimulate POMC gene expression with 3. Neuropeptides, neurotrophins, and neurotransmitters. UVA,
subsequent MSH and ACTH production in human keratin- but not UVB, irradiation increases the skin levels of met-
ocytes and endothelial cells (17, 64, 108). This stimulation of enkephalin, and multiple whole-body UVA exposure can
POMC gene expression and production of POMC peptides also increase the plasma level of the peptide (245). For its
are observed after a 10-h latency period; production becomes part, UVB induces release of CGRP, SP, and NKA from
significant at 10 –24 h (17). Of interest, humans and horses cutaneous sensory nerves (38, 108). CGRP appears to have
exposed to sunlight exhibit increases in the circulating levels immunosuppressive properties, while SP and NKA enhance
of ␣-MSH and ACTH, and experimental whole-body expo- cutaneous neuroinflammation (38, 108, 114). UVB also stim-
sure to UVR in humans increases ␤-LPH and ␤-endorphin ulates NO production by keratinocytes, melanocytes, and
serum levels (5). In the case of ␤-LPH the response is abro- NO release from sensory nerve endings (9, 108, 314). Also,
gated by UV-absorbing topical sun blockers, implicating me- UVB induces production and release of the neutrophin NGF
diation by a photoreaction (324). by epidermal keratinocytes (123, 256).
UVB can also up-regulate expression of MC1-R on normal Schallreuter et al. (334, 335) have shown that UVB enhances
and malignant cultured melanocytes and keratinocytes (5, tetrahydrobiopterin production and phenylalanine hydrox-
17, 323). This UVB up-regulation of MSH receptors expres- ylase activity, with net increase in the epidermal supply of
sion is associated in melanocytes, with increased respon- l-tyrosine. l-Tyrosine is a precursor for both catecholamine
siveness to MSH in terms of stimulation of melanogenesis, as biosynthesis and melanogenesis. Stimulation of melanogen-
shown in both cell culture and in vivo conditions (75, 323, esis by UVB is associated with increased production of the
325). These experimental findings are consistent with the biologically active products l-DOPA, dihydroxyindole
effects of exogenous MSH and ACTH in humans, which (DHI), and DHI carboxylic acid (9, 123).
cause increased skin pigmentation affecting predominantly
the sun-exposed areas. Clinically, the similarly increased B. Hair cycle
skin pigmentation of patients with Addison’s disease is most
striking in the sun-exposed areas. These experimental and Hair growth and the cyclic activity of the hair follicle are
clinical observations led Pawelek and colleagues (9, 75, 325) timed by a “biological clock,” which in rodents changes
to propose that the effects of UVB on cutaneous melanogen- periodically the physiology and morphology of the entire
esis do not represent random (unrelated) events but, instead, skin (30, 31). In mice, the expression of POMC gene and
a highly coordinated sequence in which expression of MSH production of the POMC peptides ␤-endorphin, ACTH, and
receptors and local production of POMC-derived MSH and ␣-MSH are synchronized with hair follicle cycle (5). POMC
ACTH peptides are important intermediate steps. production is lowest in telogen (resting phase), increases
during anagen (growing phase), and decreases in catagen
2. Immunoregulatory molecules. UV radiation influences the (involution phase). These changes correlate closely with the
immune system at both local and systemic levels with the net local expression of the MC1 gene (65). The intracutaneous
effect being immunosuppressive (7, 17, 64, 82, 108, 114, 326, concentration of CRH and expression of CRH-R1 exhibit
327). The mechanism for this action can be either direct similar changes coupled with the hair cycle, being highest
absorption of light energy by cells of skin immune system during anagen and lowest during the catagen and telogen
that include resident and nonresident (circulating cells) or phases (44). A similar phenomenon has been described for

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476 SLOMINSKI AND WORTSMAN Vol. 21, No. 5

SP, with maximal levels occurring in early anagen and min- context peptide hormones and neuropeptides can be degra-
imal levels occurring in catagen skin (116). Thus, the bio- dated by neutral endopeptidases (NEP) and angiotensin con-
logical clock regulating the cyclic activity of hair follicles verting enzyme (ACE), which are present in dermal fibro-
appears to regulate simultaneously the local production or blasts, endothelial cells, and keratinocytes (34, 38, 108, 337).
release of neuropeptides and the expression of the corre- NEP activity is not static, but can be stimulated by proin-
sponding receptors. flammatory cytokines, by factors raising intracellular cAMP,
The hair cycle is associated with striking changes, which and glucocorticoids (38); in addition, its cutaneous pattern of
are qualitative in distribution and quantitative in expression expression changes during wound healing (337). Other pro-
levels of the neutrophins NT-3 and NGF and their corre- teolytic enzymes such as mast cells-derived tryptase or chy-
sponding receptors in the skin of the C57 BL/6 mouse (128 – mase can degrade neuropeptides, effectively attenuating
132). Furthermore, the pattern of sensory and sympathetic their activity (7, 34, 38, 108, 115, 203).
innervation of different cutaneous structures including the Catecholamines and other biogenic amines can be inacti-
hair follicle itself, shows significant hair cycle-dependent vated directly in the epidermis, by the action of MAO and/or
changes (128, 300, 311). The changes in adrenergic innerva- by catechol-methyl transferase (21, 268, 269); the latter en-
tion are accompanied by specific patterns of follicular ␤2- zyme has been already characterized in keratinocytes and
adrenergic receptor expression. Therefore, the whole cuta- melanocytes. Acetylcholine is degraded to acetate and cho-
neous neural network involved in the regulation of hair line by epidermal acetylcholinesterase (20, 259). The skin is,
growth undergoes cyclic changes (128, 300, 311), which can in addition, a well recognized site for the transformation of
potentially affect the function of other cutaneous structures, glucocorticoids and sex hormones to molecular forms with
sensory skin responsiveness, and transmission of afferent higher or lower hormonal activity, or overtly inactive (4, 11,
signals to the spinal cord. Because of the extent and magni- 160, 297).
tude of the hair cycle-dependent changes, it is likely that
these are regulated within the skin itself, under the control
of the “biological clock” governing hair cycle. VII. Regulation of Cutaneous Vitamin D Production
A. Vitamin D3 production
C. Cytokines
The recognition that the skin could react with an invisible
Similar to its effects at the central level, the proinflamma- component of sunlight to make a factor indispensable for the
tory IL-1 has significant local stimulatory/inductory effects mineralization of bone vitamin D represents a remarkable
on POMC gene expression and production of POMC pep- scientific accomplishment (14). Vitamin D3, or cholecalcif-
tides in normal and malignant epidermal melanocytes and erol, is formed from the precursor steroid 7-dehydrocholes-
keratinocytes, dermal endothelial cells, and circulating im- terol (7-DHC), which is normally concentrated to the plasma
mune cells that include macrophages (5, 17, 64, 108, 230). membrane of basal epidermal keratinocytes (80% of skin
Another cytokine, TNF␣, stimulates production of POMC content). Upon stimulation with sunlight photons of UVB
mRNA in normal dermal fibroblasts, while TGF-␤ inhibits it light (290 –310 nm wavelength), 7-DHC undergoes photo-
in keratinocytes and normal dermal fibroblasts, but not in lysis with breakage of the 9,10-carbon bond generating the
keloid fibroblasts (231). TNF␣ also stimulates production of thermolabile intermediate previtamin D3. At normal skin
the POMC products ␤-endorphin and ACTH peptides (336). temperature previtamin D3 molecules convert into vitamin
Many cytokines can up-regulate expression of the MC-1 gene D3 through internal rearrangement (Fig. 7). Vitamin D3 en-
and of functional cell surface MSH receptors in normal and ters the circulation bound with high specificity to vitamin D
malignant melanocytes (5, 17, 64, 323). Those include Il-1␣, binding protein (DBP) to exert its systemic actions (338).
IL-1␤, endothelin-1 (ET-1), adult T cell leukemia-derived When newly formed previtamin D3 and vitamin D3 continue
factor/thioredoxin (ADF/TRX), INF-␣, INF-␤, INF-␥, to be irradiated, they convert into additional steroids such as
(Bu)2cAMP, and the hormones ␣-MSH, ␤-MSH, and ACTH. lumisterol, pyrocalciferol, and tachysterol, which are prac-
IL-1 can also stimulate MC-1 receptor expression in normal tically devoid of vitamin D3 activity (14). Although light and
and malignant human keratinocytes and in human dermal temperature are the only variables involved in the biosyn-
microvascular endothelial cells (HDMEC) (17, 64, 230). Con- thetic process, they do not account entirely for the rates of
versely, TNF␣ inhibits MC1 expression in melanocytes. biosynthesis observed in tissues. Thus, irradiation of 7-DHC
Thus, selected cytokines regulate precisely (“fine-tuning”) dissolved in isotropic organic solvents such as hexane gen-
the level of expression of POMC and MC1-R. The roles of erates only one tenth of the amount observed in similarly
cytokines in the cutaneous regulation of epidermal cholin- irradiated skin (14). The explanation for this discrepancy was
ergic system, production of catecholamines, steroid synthesis obtained in experiments with artificial liposomes, which un-
and metabolism, and synthesis of neuropeptides CRH, uro- covered the crucial role played by plasma membrane phos-
cortin, and enkephalins remain to be investigated. pholipids in the kinetics of the reaction. Thus, through am-
phipatic interactions, previtamin D3 remains stabilized in its
D. Degradation or inactivation of hormones and “cholesterol like” cZc– conformation, the only one leading to
neurotransmitters conversion to vitamin D3. Furthermore, the fastest rate of
previtamin D3 isomerization was seen in association with
One important mechanism regulating the availability of phospholipids containing 18 carbon atoms in the hydrocar-
locally produced hormones is their degradation in situ. In this bon chain (339).

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October, 2000 NEUROENDOCRINOLOGY OF THE SKIN 477

FIG. 7. Cutaneous synthesis of vitamin D3. Under exposure to UVB, cutaneous 7-dehydrocholesterol molecules undergo photolysis to the
secosteroid product cZc-previtamin D3 (this cis-conformer is the only form that can be converted into vitamin D3). Thermal energy produces
intramolecular rearrangement of cZc-previtamin D3 with a 1,7-sigmatropic hydrogen transfer from C-19 to C-9, to yield vitamin D3. [Modified
from X. Q. Tian and M. F. Holick: J Biol Chem 274:4174 – 4179, 1999 (339), by permission from the Journal of Biological Chemistry. © The
American Society for Biochemistry and Molecular Biology.]

Once formed in the skin, vitamin D is translocated to the respectively, by black polyester, black cotton, white cotton,
circulation over a period of 30 h or longer. It reaches pe- white wool, and white polyester. All of the fabrics produced
ripheral tissues bound with high specificity (98%) to vitamin significant attenuation of the shorter wavelengths (UVB),
D binding protein (also known as group-specific component and studies in volunteers wearing garments made of the
or GC). This is in contrast to orally derived vitamin D2 (er- same materials showed complete obliteration of the normal
gocholecalciferol), which circulates only 50% bound to vita- serum vitamin D3 photosynthetic response to one MED (min-
min D binding protein, with the remaining fraction being imal erythema dose) of UVB (341). This absence of vitamin
bound to cholesterol containing lipoproteins (14). Vitamin D D serum response persisted after whole-body irradiation was
is metabolized (activated) to 25-hydroxyvitamin D (in the increased to the equivalent of 6 MEDs. In addition, regular
liver) and to 1,25 dihydroxyvitamin D (in the kidney) (14). street clothing, even that worn during summer, also pro-
According to the level of action, the physiological and patho- duced significant suppression of the vitamin D3 response to
logical factors that modify the systemic supply of cutaneous UVB (341).
vitamin D3 can be classified into precutaneous, cutaneous,
b. Sunscreens. These agents prevent skin penetration of
and postcutaneous.
solar radiation. Thus, PABA (para-aminobenzoic acid), the
common active ingredient of sunscreens, has an absorption
B. Precutaneous regulation spectrum that overlaps the spectrum responsible for the pho-
1. Environment dependent. This category includes geographic tosynthesis of vitamin D3 (342). As would be expected, ap-
latitude. Thus, as the earth experiences its seasonal tilting plication of PABA to skin pieces blocked the conversion of
during fall and winter, sunlight arrives at an angle at the 7-DHC to previtamin D3 that normally follows exposure to
more polar latitudes crossing the atmosphere almost tan- simulated sunlight. Moreover, in healthy volunteers, cover-
gentially during winter, and lessening transmission of UVB age of the whole body with sunscreens abolished the serum
wavelengths. For example, during winter in Boston, Massa- vitamin D3 response to UVB light delivered in a photother-
chusetts (latitude 42.2 oN) these wavelengths disappear apy unit (342). Also patients with photodependent cutaneous
(339), and a similar situation is observed in the Southern disorders such as skin cancer, who must use sunscreen
Hemisphere, where vitamin D3 photosynthesis is extremely chronically, have lower serum levels of 25-hydroxyvitamin
low during winter in Cape Town, South Africa (latitude D as compared with matched controls (343). Nevertheless, it
35oS), but almost unchanged throughout the year in Johan- must be noted that these lower 25-hydroxyvitamin D levels
nesburg (26oS)(340). Another environmental variable is the have not been associated with secondary hyperparathyroid-
time of day, since vitamin D3 synthesis is maximal at midday, ism or metabolic bone disease (344).
with only very small amounts being formed before 0800 h or
after 1700 h. In fact, in Cape Town, only negligible amounts C. Cutaneous regulation
of previtamin D3 are formed in the winter before 0010 h and
1. Regional (anatomical) activity of solar radiation. The segmen-
after 1500 h. In general, latitude, season of the year, and time
tal body contributions to the supply of vitamin D3 were
of day affect the cutaneous photosynthetic process in a highly
evaluated in healthy individuals who had sunscreens ap-
coordinated, mutually dependent manner (14).
plied to selected areas of the body before UVB irradiation
2. Environment independent. (345). Significant and almost equivalent serum vitamin D3
increases occurred after selective irradiation of either trunk,
a. Clothing. Garments provide significant protection legs, or the entire body. UVB exposure of only the head and
against the damaging effects of solar light that include ery- neck or arms produced a lesser rise in vitamin D3 serum
thema, accelerated aging, and development of skin cancer. levels, which did not reach statistical significance (345).
Experiments on transmission of UVB light through different
fabrics showed significant effects on the photosynthesis of 2. Race-related skin pigmentation. Melanin is not a “neutral
vitamin D3 (341). Of fabrics with similar thread density, black density” light filter, but exhibits varying absorption coeffi-
wool had the highest light absorption coefficient followed, cients, with maximal absorption for the shorter wavelengths

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478 SLOMINSKI AND WORTSMAN Vol. 21, No. 5

of the spectrum (⬃ 300 nm) (346). Thus, melanin has a sig- responses in patients and controls. Moreover, the responses
nificant effect on the synthesis of vitamin D3. As would be were unrelated to the extent of cutaneous involvement.
expected, the highest vitamin D3 response to UVB is seen in These results probably reflect the small fraction of irradiated
white individuals, followed by Orientals (East Asians) and body surface required to sustain the normal vitamin D3 re-
Indians (South Asians) and is extremely attenuated in blacks quirements. A small fraction of vitamin D3 formation does
(African Americans) (347). This race effect is also associated occur in the dermis (⬍10%), which has a much lower 7-DHC
with lower prevailing levels of 25-hydroxyvitamin D, al- content than the epidermis and is less exposed to the low-
though the serum concentrations of 1,25-dihydroxyvitamin penetrance shorter light wavelengths responsible for vitamin
D are similar among race groups. The latter results from the D3 formation. As mentioned above, the dermal disease, pro-
intrinsic properties of the renal enzyme l␣-hydroxylase, gressive systemic sclerosis, even when widespread, does not
which can compensate for wide differences in availability of interfere with the vitamin D3 response to UVB (356).
25-hydroxyvitamin D (348). Asian Indian individuals, who
have additional peculiarities in their vitamin D metabolism, D. Postcutaneous regulation
are particularly sensitive to the development of clinical
vitamin D deficiency, rickets and osteomalacia, when living 1. Obesity. Overweight appears to represent the only post-
in areas with low levels of ambient sunlight (349). cutaneous factor interfering with vitamin D3 photosynthesis.
The UVB light threshold that produced measurable syn- Obese individuals have lower serum 25-hydroxyvitamin D
thesis of vitamin D3 was 18 mjoules/cm2 in a population of levels than lean controls and also have blunted response to
white subjects with similar cutaneous photosensitivity (skin UVB. Oral absorption of vitamin D2 is also decreased in
type III of the Fitzpatrick-Pathak classification; 1 MED⫽30 obesity. In vitro experiments of irradiation of skin pieces from
mjoules/cm2), although every dose tested was associated obese and lean individuals showed similar epidermal 7-DHC
with blood levels higher than baseline (350). Serum GC is content and in vitro response to UVB. These results are sug-
another factor involved in the availability of vitamin D3 that gestive of defective translocation of the vitamin into the
could be race dependent. Thus, anthropologists have iden- circulation, or defective plasma transport (357). Of note, obe-
tified a large number of variants, each related to different sity is also associated with increases in plasma FFA, which
human populations. By isoelectric focusing, the observed GC can displace vitamin D3 from plasma vitamin D binding
suballele frequencies appear to correlate with skin pigmen- protein (358).
tation, but electrophoretically identical variants were also
found in populations widely differing genetically and geo-
E. General comments
graphically (351). From the functional point of view, there is
no evidence for differences in vitamin D binding among An important consideration on the physiology of vitamin
those variants. Moreover, the serum concentration of GC is D3 synthesis is that it represents a mostly biophysical reac-
similar across race groups that include blacks, whites, Ori- tion. Thus, the serum vitamin D3 response to UVB is not
entals, and Asian Indians (347). altered by the oral administration of pharmacological doses
of vitamin D2 (359) or of 1,25-dihydroxyvitamin D (360).
3. Suntanning. In the setting of suntanning, vitamin D3 for- There are nevertheless local regulatory mechanisms that can
mation is affected in a complex manner. As already men- influence the process. When exposure to sunlight is exces-
tioned, both previtamin D3 and vitamin D3 are photosensi- sive, inactivation of previtamin D3 and vitamin D3 itself are
tive substrates that, if irradiated continuously, undergo well known consequences. Moreover, when high irradiance
further conversion to inactive metabolites while still in the levels are sustained, melanocyte activity is enhanced, result-
skin (14). Nevertheless, measurements performed in tanned ing in tanning and blunted response to acute UVB exposure.
white subjects showed elevated vitamin D3 serum levels with The opposite situation, decreased exposure to UVB with
correspondingly higher serum 25-hydroxyvitamin D con- reduced vitamin D3 production, can be compensated, at least
centration (352). Acute exposure to UVB radiation resulted, partly, by enhanced activity of the renal 1␣-hydroxylase en-
however, in attenuated serum vitamin D3 response, presum- zyme (348).
ably the result of acquired cutaneous melanization (352). Lastly, there has been some controversy regarding the
4. Aging. Elderly individuals have lower serum levels of significance of findings in acute vs. chronic studies evaluat-
25-hydroxyvitamin D as compared with their younger coun- ing the vitamin D response to UVB. Within this context, it
terparts. This aging effect is due to progressive decrease in must be noted that acute studies are performed under more
epidermal 7– dehydrocholesterol substrate content (353). As stringent conditions, i.e., mostly during the winter, to prevent
would be expected, acute irradiation with UVB in older sub- the interference of ambient sunlight, which involves expo-
jects results in blunted serum vitamin D3 responses (354). sure of the whole body to UVB, and require a phototherapy
unit that must be continuously calibrated. It is then apparent
5. Cutaneous disease. The only cutaneous disorders in which that biological significance is better evaluated in larger pop-
vitamin D3 formation has been systematically studied are the ulations. Thus, small acute responses that do not reach sta-
epidermal disease, psoriasis (355), and the connective tissue tistical significance, such as those observed after selective
disease, progressive systemic sclerosis (356). The latter, al- irradiance of the upper extremities or head and neck, or after
though predominantly a dermal disorder, is often associated subthreshold doses of UVB, may still result in normal vita-
with epidermal atrophy. Acute irradiation experiments in min D3 levels, when irradiation is continued through much
these two groups of patients did show similar vitamin D3 longer periods. A similar explanation would be operative in

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October, 2000 NEUROENDOCRINOLOGY OF THE SKIN 479

black individuals, who show lack of response to acute UVB get conditions include not only inflammatory diseases, but
irradiance, yet also exhibit the normal seasonal variance benign hyperproliferative skin disorders, vasculopathic and
(UVB dependent) in 25-hydroxyvitamin D serum levels autoimmune reactions, disorders of pigmentation and hair
(361). cycling, and malignant processes such as melanoma devel-
opment and epidermal carcinogenesis. Specifically, locally
produced POMC peptides ACTH and ␣-MSH can affect skin
functions by enhancing melanogenesis, stimulating hair
VIII. Final Comments and Future Directions
growth and sebaceous gland functions, and attenuating in-
The present work provides a conceptual framework for the flammatory responses. CRH, in addition to its local vasodi-
organization of the cutaneous neuroendocrine system into latory and proinflammatory effects, may also inhibit prolif-
epidermal and dermal units. Further, it develops an under- eration of epidermal keratinocytes. Vitamin D is already
standing of the integrated pattern of regulation of those used in the therapy of psoriasis, and glucocorticoids are
endocrine units, and of the exquisite coordination in expres- drugs of choice in the treatment of inflammatory skin dis-
sion of their functional effects to achieve the best strategy for orders. Finally, the multidirectional communication between
dealing with the continuous interactions between skin and skin, endocrine, immune, and central nervous systems sug-
environmental agents. Among the recently uncovered reg- gests that the skin may be an important regulator of global
ulatory mechanisms are a myriad of precise interactions with homeostasis acting as a sensor for external or internal dis-
receptors for hormones, neurotransmitters, and neuropep- turbances, and as an effector/producer of humoral or neural
tides, e.g., hypothalamic, pituitary, and steroid hormones, signals sent to other coordinating centers. In this context, the
PTH and PTHrP, vitamin D, neuropeptides, neurotrophins, possibility of pathological consequences for dysregulation in
and with nicotinic, muscarinic, adrenergic, serotonin, and this cutaneous neuroendocrine system poses a powerful
glutamate neurotransmitter receptors, all widely expressed challenge that can only be addressed with a strong, coordi-
in cutaneous compartments. Surprisingly, the source of li- nated, and multidisciplinary approach.
gands for these receptors is the skin itself, sometimes the
same histological compartment, or even the same cells. Thus,
the conclusive documentation now available demonstrates Acknowledgments
that in addition to vitamin D3, the skin produces PTHrP, We thank Drs. C. Gomez-Sanchez, O. Johansson, W. B. Malarkey, J.
CRH, urocortin, POMC-derived peptides, enkephalins, cat- Orloff, M. F. Holick, S. Asa, D. L. St. Germain, S. Grando, T. Smith, E.
echolamines, acetylcholine, and neurotrophins. The skin is Wei, and L. Y. Matsuoka for their help in the preparation of the manu-
also involved in steroidogenesis and sex hormone conver- script. The excellent secretarial work of Ms. LuEllen Giera is acknowl-
edged.
sion. Intriguing experimental data showing interconversion
of thyroid hormones, however, require further confirmation.
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