Sie sind auf Seite 1von 8

Cytokine 81 (2016) 1522

Contents lists available at ScienceDirect

Cytokine
journal homepage: www.journals.elsevier.com/cytokine

Review article

The role of IL-18 in type 1 diabetic nephropathy: The problem and future
treatment
Nehal M. Elsherbiny a, Mohammed M.H. Al-Gayyar a,b,
a
b

Department of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia

a r t i c l e

i n f o

Article history:
Received 7 December 2015
Received in revised form 21 January 2016
Accepted 24 January 2016

Keywords:
Type 1 diabetes mellitus
Diabetic nephropathy
Renal complications
IL-18
IL-18 binding protein

a b s t r a c t
Diabetic vascular complication is a leading cause of diabetic nephropathy, a progressive increase in urinary albumin excretion coupled with elevated blood pressure leading to declined glomerular filtration
and eventually end stage renal failure. There is growing evidence that activated inflammation is contributing factor to the pathogenesis of diabetic nephropathy. Meanwhile, IL-18, a member of the IL-1 family of inflammatory cytokines, is involved in the development and progression of diabetic nephropathy.
However, the benefits derived from the current therapeutics for diabetic nephropathy strategies still provide imperfect protection against renal progression. This imperfection points to the need for newer therapeutic agents that have potential to affect primary mechanisms contributing to the pathogenesis of
diabetic nephropathy. Therefore, the recognition of IL-18 as significant pathogenic mediators in diabetic
nephropathy leaves open the possibility of new potential therapeutic targets.
2016 Elsevier Ltd. All rights reserved.

Contents
1.
2.
3.

4.
5.
6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Diabetic nephropathy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Diabetic nephropathy and inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
IL-18 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Signaling pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.
Biological functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
IL-18 in diabetic nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Therapeutic strategies for reducing interleukin 18 activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abbreviations: COX-2, cyclooxygenase-2; DN, diabetic nephropathy; ICAM-1,


intracellular adhesion molecule-1; IL-18BP, IL-18 binding protein; IRAKs, IL-1Rassociated kinases; MAPK, mitogen-activated protein kinase; MCP-1, monocyte
chemotactic protein-1; MyD99, myeloid differentiation 88; NFkB, nuclear factor kB;
NIK, NFkB-inducing kinase; NK, natural killer; NO, nitric oxide; Th, T helper cells;
TNF, tumor necrosis factor; TRAF-6, tumor necrosis factor receptor associated
factor; TLR, Toll-like Receptor; UAE, urinary albumin excretion; VCAM-1, vascular
cell adhesion molecule-1.
Corresponding author at: Department of Pharmaceutical Chemistry, Faculty of
Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia.
E-mail address: mhgayyar@yahoo.com (M.M.H. Al-Gayyar).
http://dx.doi.org/10.1016/j.cyto.2016.01.014
1043-4666/ 2016 Elsevier Ltd. All rights reserved.

15
16
16
17
17
17
17
17
18
19
19
20
20

1. Introduction
Considered as a leading reason for end-stage renal failure, diabetic vascular complications account for high mortality rates
occurs in patients with diabetes [1]. Patients with diabetic kidney
are at high risk of developing both renal disease and cardiovascular
morbidity and mortality [2]. Chronic hyperglycemia induces
abnormal pathology of various renal cells, which contributes to
renal dysfunction in diabetes. High glucose plays detrimental role

16

N.M. Elsherbiny, M.M.H. Al-Gayyar / Cytokine 81 (2016) 1522

Table 1
Causes of diabetic nephropathy.
Factors causing diabetic
nephropathy
Metabolic factors

Reference
Advanced glycation end products
Aldose reductase/polyol pathway
Diacylglycerol (DAG)-protein kinase
C (PKC) pathway
Reactive oxygen species

[10]
[11]
[12]

Activation of rennin angiotensin


system
Endothelin
Nitric oxide

[14]

Intracellular factors

Nuclear factor-kB (NF-KB)

[17]

Growth factors and


cytokines

Transforming growth factor-b


Growth hormone and insulin like
growth factor
Vascular endothelial growth factor
Platelet derived growth factor

[18]
[19]

Hemodynamic factors

[13]

Altered
shear
stress

Systemic and
intraglomerular
hypertension

Mechanical
strain
Advanced
glycaon
end products

Hemodynamic
abnormalies
Metabolic
derangements

Hyperglycemia

[15]
[16]

Hyperlipidemia

Diabec
renal injury
Angiotensin II

[20]
[21]

Hormones
in development and progression of diabetic renal complications via
various signaling pathways such as increased production of
advanced glycation end products, expression of protein kinase C,
activation of the polyol pathway and generation of reactive oxygen
species [1,36].
2. Diabetic nephropathy
Diabetic nephropathy (DN) is a syndrome defined as a progressive increase in the excretion of urinary albumin (UAE), elevated
blood pressure coupled with glomerular lesions leading ultimately
to loss of glomerular filtration and eventually end stage renal failure [7]. DN remains the most prevalent chronic disease of the kidney. It is reported that about one third of patients with diabetes
develops nephropathy. In addition, about 2540% of type 1 diabetic
patients develop DN within 2025 year of diabetes [8]. Multiple
mechanisms contribute to the development of DN. Sustained
hyperglycemia and hypertension are the most important factors
in the initiation and progression of nephropathy. Some of these
mechanisms were summarized in Table 1. Regardless of multiple
researches conducted on molecular and clinical basis, only
partial protection is obtained by the available standard therapy
that targets reninangiotensinaldosterone system by using
angiotensin-converting enzyme inhibitors and/or angiotensinreceptor blockers [9]. Therefore, new and effective therapeutic
approaches are required especially with the alarming increase of
diabetes globally.
2.1. Diabetic nephropathy and inflammation
There is growing proof that both activated innate immunity and
inflammation engage to pathogenesis of diabetic nephropathy [22].
Therefore, multiple cells, including leukocytes, monocytes and
macrophages as well as other molecules such as chemokines,
adipokines, adhesion molecules, enzymes like cyclooxygenase-2
and nitric oxide synthase, receptors like toll-like receptors and
nuclear receptors, growth factors and nuclear factors like nuclear
factor jB (NFjB) are all implicated in processes related to diabetic
nephropathy [23]. Inflammation plays vital role in the process of
fibroblast activation and subsequent tissue fibrosis; the most fundamental and distinguished feature of DN. Therefore, inflammatory pathways that are activated by the different metabolic,
hemodynamic and physiological factors appear to be critically
involved in the development and progression of DN [24]. Further
support for the contribution of inflammation to diabetic renal
injury comes from studies where the use of immunosuppressive

Sex hormone

External noxious or
proinammatory factors
Growth
hormone

Smoking
Obesity

Dietary
factors

Fig. 1. Factors associated with diabetic renal injury that induced the activation of
diverse signal transduction systems in kidney cells.

strategies declined the accumulation of renal macrophage leading


to attenuation of the development of DN [2527].
Hyperglycemia, advanced glycation products and other components of diabetic milieu induce activation of renal cells, which lead
to expression of numerous compounds such as chemokines, adhesion molecules and proinflammatory cytokines. Collectively, these
incidents contribute to renal cell injury and subsequent gross
anatomical and functional alteration associated with DN including
albuminuria, mesangial expansion, thickening of glomerular basement membrane, tubulointerstitial damage and fibrosis [28]. The
factors associated with diabetic renal injury were summarized in
Fig. 1.
It is now widely accepted that accumulation of inflammatory
cell in the kidney is a key player in the induction of DN [29].
Indeed, blocking the recruitment of inflammatory cells to the kidney has been proved to protect against renal injury in animal models of DN [30]. Pro-inflammatory cytokines that are produced by
inflammatory cells directly damage kidney architecture [31].
Cytokines are pleiotrophic low molecular weight polypeptides,
which can produce autocrine, paracrine and juxtacrine effects.
Cytokines play crucial role in regulating which inflammatory and
immune responses. The role of Cytokines inflammatory and
immunologic pathways in the pathogenesis and progression of
DN is well documented [32]. The major pro-inflammatory cytokines that have been reported to play a pivotal role in the pathogenesis of DN are interleukin (IL)-1, IL-6, IL-18 and tumor necrosis
factor (TNF)-a. All these cytokines are increased in DN. Moreover,
the elevated serum and urine levels of pro-inflammatory cytokines
correlates with the progression of DN. Furthermore, gene polymorphism of both the pro-inflammatory cytokines and their receptors
can be used as strong predictor of the susceptibility and progression of DN [33]. Indeed, targeting cytokines and/or their receptors
ameliorated DN, implying significance of cytokines as key players
involved in DN pathophysiology [34].

N.M. Elsherbiny, M.M.H. Al-Gayyar / Cytokine 81 (2016) 1522

Each cytokines has variable effects. For example, IL-1 augments


the expression of chemokines and adhesion molecules, stimulates
prostaglandin E2 formation leading to alteration in glomerular
hemodynamic, elevates vascular endothelial cell permeability,
enhances mesangial and fibroblast proliferation by induction of
TGFb-1 production and increases glomerular cellularity by elevating hyaluronan production by epithelial cells of renal proximal
tubule [35,36].
IL-6 contributes to progression of DN by enhancing extracellular
matrix accumulation and proliferation leading to glomerular basement membrane thickening [37]. In addition, it alters endothelial
permeability and mesangial cell expansion [38]. TNF-a causes
direct renal injury as a cytotoxin on glomerular podocytes and
tubular cells resulting in apoptosis as well as necrotic cell death
[39]. Moreover, IL-6 stimulates ROS production with subsequent
cellular damage [40]. Of note, it magnifies the renal inflammatory
response by stimulating production of other inflammatory cytokines, adhesion molecules and chemokines leading to worsening of
the progression of DN [41]. IL-6 may disrupt renal blood flow,
affect glomerular hemodynamics and endothelial permeability by
disrupting endothelial intercellular junctions and consequential
integrity of the glomerular filtration barrier [28].
IL-18 is a potent inflammatory cytokine. IL-18 is produced by
both inflammatory cells and parenchymal kidney cells (tubular
epithelial cells, podocytes and mesangial cells). IL-18 directly damages kidney cells as well as it activates production of other inflammatory cytokines, such as IL-1, interferon c and TNF [42]. Despite
the large literature on the role of IL-18 in the pathogenesis of different kidney diseases, studies need to determine whether IL-18 is
a suitable target for therapeutic intervention to ameliorate the progression of DN.

3. IL-18
IL-18 is a member of the IL-1 family of cytokines. It exhibits significant sequence homology with both IL-33 and IL-1b [43]. It was
first described in 1989 as an IFN-c-inducing factor in the circulation of mice following endotoxin injection [44]. With the molecular
cloning of IFN-c-inducing factor in 1995, the name was changed to
IL-18 [45]. IL-18 is produced as a biologically inactive precursor
and stored in cytosol. Activation of IL-18 occurs after processing
by group I caspases or inflammatory caspases [46,47]. Caspases
are produced as zymogens and need inflammasome to be activated. Therefore, the activation and release of IL-18 to exert its
pro-inflammatory effect is dependent on both caspase 1 and
inflammasome activation [48]. In addition, IL-18 was reported to
be produced via caspase 1 independent non-canonical mechanisms
including other caspases like 3 and 8, granzyme B, proteinase 3,
and merpin-b [49]. IL-18 is produced in almost all human cells,
including macrophages, microglial cells, endothelial cells, vascular
smooth muscle cells, dendritic cells, Langerhans cells, Kupffer cells,
adipocytes, chondrocytes, intestinal epithelial cells and synovial
fibroblasts and osteoblasts [5053].

3.1. Structure
IL-18 is a single non-glycosylated peptide chain with a molecular weight of 18 kDa. IL-18 precursor is synthesized as polypeptide
of 192 amino acids with a molecular weight of 24 kDa, which is
cleaved enzymatically to 18 kDa mature IL-18 consisting of 157
amino acids. IL-18 protein adopts a conserved b-trefoil folded
structure that is made up of twelve packed b-sheets (b1b12)
and two a-helices (a1a2) [54]. In this regard, IL-18 shows structural similarity to IL-1b and IL-33 [43]. The IL-18 structure is

17

unique because few cytokines exist as all b-pleated sheet folded


molecules [55].
3.2. Receptors
Members of IL-1 receptor family and Toll-like Receptor have
been assorted into one family, called the Interleukin-1 Receptor/
Toll-like Receptor (IL-1R/TLR) superfamily. Off note, it was found
that IL-18 shares downstream signaling with TLR, which are in turn
involved in regulating IL-18 expression [56]. IL-18R heterodimer
complex consists of two receptor chains: IL-18Ra (also known as
IL-1Rrp1, IL-18R1 or IL-1R5) which is a ligand-binding chain and
a coreceptor termed IL-18Rb chain (also called IL-18RacP, IL18RII or IL-1R7); both chains have three amino terminal extracellular Ig-like domains and one intracellular carboxy-terminal region
which have Toll/IL-1 receptor (TIR) domain [57]. The a chain is
responsible for extracellular binding ability, and the b chain is
responsible for intracellular signal transduction. IL-18Rb chain is
genetically different but structurally related to IL-18Ra. Binding
of IL-18 to a chain leads to recruitment of the non-binding IL18Rb
chain, ultimately forming high-affinity heterotrimeric complex.
Although both free and protein-bound forms of IL-18 might bind
to the a chain, only the free fraction of IL-18 is able to activate
the b chain [58]. IL-18 receptor complex expression is regulated
by various cytokines that exhibit synergistic effect with IL-18 on
IFN-c production, including IL-12, IL-23, IL-21, IL-2 and IL-15 [59].
3.3. Signaling pathways
IL-18 activity is initiated by ligand binding to its receptor complex. First, IL-18 binds to the low affinity (about 10 nM) IL-18Ra
chain and secondly, non-binding signal-transducing b-chain is
recruited to the complex, forming high-affinity complex in which
TIR domains within the intracellular regions of each receptor chain
become into close proximity. This enhances the recruitment of
cytosolic protein myeloid differentiation 883 (MyD88), IL-1Rassociated kinases (IRAKs) followed by interaction with TNF receptor associated factor (TRAF)-6 [60]. MyD88 binds to IL-18 complex
via the TIR domain. MyD88 functions as an adapter or anchoring
molecule, assisting in the binding and autophosphorylation of
the IRAKs. IRAK then dissociates from the IL-18R complex and
associates with TRAF-6, which in turn phosphorylates NFkBinducing kinase (NIK) that in turn phosphorylates IjB [59,61].
Phosphorylated IjB is rapidly degraded by the ubiquitin pathway,
leading to NFjB liberation and translocation to the nucleus for
gene transcription. The signaling pathway of IL-18 was summarized in Fig. 2. In addition to MyD88-dependent signaling, IL-18
has also been found to signal via alternative pathways including
Map Kinase, tyk-2, STAT3 and NFATc4 [62].
3.4. Biological functions
IL-18 has pleiotropic immunoregulatory functions affecting
both innate and acquired immune responses. IL18 acts in collaboration with other cytokines to regulate the immune system
responses. IL-18 amplifies IFN-c production in synergy with other
Th1-related cytokines, IL-2, IL-15, IL-12 and IL-23. In addition, IL18 stimulates natural killer (NK) cell maturation alone or in combination with IL15 [63]. Indeed, it was found that IL-18, in concert
with IL-12 and IL-15 consolidates the production of TNF-a, GMCSF, and the chemokines CCL3 and CCL4 by NK cells [64]. Moreover, IL-18 enhances FasFasL-mediated cytotoxicity of NK cells
by upregulation of FASL expression on NK cells [63].
IL-18 induces activation, degranulation and release of cytokine
from neutrophils and facilitates maturation and activation of
monocytes [61,65]. Further, IL-18 enhances cytokines-mediated

N.M. Elsherbiny, M.M.H. Al-Gayyar / Cytokine 81 (2016) 1522

Caspase-1

IL-18

IL-18R

Pro-IL-18

IL-18R

18

IL-18R
MyD88

IRAKs

TRAF6

MAPK

apoptotic
pathway

NFB

gene
transcription

Fig. 2. Signaling pathway of IL-18. IL-18R, interleukin-18 receptor; MyD88, myeloid differentiation 88; IRAKs, IL-1R-associated kinases; TRAF6, tumor necrosis factor receptor
associated factor-6; NFkB, nuclear factor kB; MAPK, Mitogen-activated protein kinases.

activation of T cells and macrophages through enhancing cellcell


interactions between both types of cells [66]. In CD4+ lymphocytes,
IL-18 can stimulate both type 1 helper T (Th1) and Th2 responses
depending on its cytokine environment [67]. In absence of IL-12
and IL-15, IL-18 activates a Th2 response in combination with IL2. On the other hand, it may act synergistically with IL-12 to trigger
Th1 response. Moreover, in synergy with IL-23, IL-18 enhances the
production of IL-17 by Th17 cell [68]. On non-T cell populations, IL18, in conjunction with IL-3, induces the production of IL-4 and IL13 by bone marrow-derived basophils NK cells and mast cells [69].
IL-18 displays pro-inflammatory aspects including increase the
production of cell adhesion molecules, chemokines and nitric oxide
synthesis. It potentiates TNF-a production by mononuclear and
mesenchymal cells [70]. Moreover, it upregulates inducible nitric
oxide (NO) synthase, chemokines such as CXCL8, CXCL5 and
CCL20 [71] and cyclooxygenase (COX)-2 expression [72]. It is also
suggested that IL-18 up-regulates the expression of intracellular
adhesion molecule (ICAM)-1, vascular cell adhesion molecule
(VCAM)-1 and matrix metalloproteinases-1, -9, and -13 in
endothelial cells and synovial fibroblasts [73,74]. Therefore, it is
not surprising that Il-18 is involved in multiple autoimmune
and/or inflammatory diseases including colitis, rheumatoid
arthritis, ischemia reperfusion injury, hepatitis, insulin dependent
diabetes
mellitus,
Allergic
airway
hyperresponsiveness,

Ischemia-induced renal failure, hepatic failure and myocardial


dysfunction [75].
4. IL-18 in diabetic nephropathy
IL-18 is fundamentally expressed in renal tubular epithelial
cells. Besides, infiltrating monocytes, macrophages, T lymphocytes
and proximal tubular cells, are all potential sources of this cytokine
[76,77]. IL-18 has been shown to participate in renal injury in
experimental models of renal disease including ischemia
reperfusion injury [78], lupus nephritis [79], nephropathy [80],
glomerulonephritis [81] and hypertension [48] through activation
of iNOS, TNF-a, IFN-c, MCP-1 and other chemokines leading to
macrophage and neutrophil infiltration, glomerulosclerosis and
tubular necrosis. Of note, IL-18 was reported to be upregulated in
podocytes, interstitial myofibroblasts, infiltrating interstitial
macrophages and tubular epithelial cells in different kidney disease models [76,82]. In diabetic patients, the serum and urinary
concentrations of IL-18 have been reported to be significantly elevated with an independent association with urinary albumin
excretion and b-2 microglobulin [83,84]. Moreover, in a prospective investigation, IL-18 accumulation in both serum and urine
were directly associated with the UAE as well as with alteration
in albuminuria during the follow-up period [84]. The independent

19

N.M. Elsherbiny, M.M.H. Al-Gayyar / Cytokine 81 (2016) 1522


Table 2
Summary of reports that examined IL-18 in relation to various renal cells under diabetic condition.
Model

Summary

Cell type

References

Human

IL-18 helps the progression of nephropathy by affecting kidney


function directly as well as its proinflammatory effect
IL-18 was overexpressed in human tubular epithelial cells in
diabetic nephropathy through activation of MAPK pathways
induced by TGF-b1
Elevated serum and urinary IL-18 in patients with type 2 diabetes
compared with healthy controls. There is a positive correlation
between IL-18 levels in diabetic patients and the development of
urinary albumin excretion
Urinary IL-18 is associated with albuminuria in the early stage of
nephropathy in type 2 diabetics and may reflect inflammatory
processing

Serum

[96]

Tubular epithelial cells

[85]

Serum

[83,84,97,98]

Urine

[99]

Rat renal tissue

[93,100102]

Mouse renal tissue/mouse


glomerular endothelial cells

[103]

Mouse renal tissue/mouse podocytes

[94]

Diabetic rodents

Diabetic nephropathy is associated with elevated protein and


gene expression of IL-18
Protein and mRNA levels of IL-18 was significantly increased in
diabetic mouse renal tissue as well as mouse glomerular
endothelial cells treated with high glucose
Targeting inflammasome/IL-1b/IL-18 axis by knocking out
purinergic 2X7 receptor (P2X7R) reduced renal inflammation and
fibrosis in a high-fat diet fed mice

correlation of IL-18 with clinical markers of glomerular and tubulointerstitial damage suggests that this potent cytokine may be a
pathogenic factor for the development and progression of DN.
Indeed, elevated levels of IL-18 are determinant of early renal dysfunction in patients with diabetes [42]. Moreover, this cytokine has
been proposed to have support role to progression of DN, rather
than other diabetic complications [85]. Several studies reported
elevated serum levels of IL-18 in patients with chronic kidney diseases, especially those with declined GFR [86,87] and attributed to
high percentage of active monocytes, the main cellular source of
this cytokine [88]. Intracellularly, IL-18 can promote the production of pro-inflammatory cytokines and chemokines by mesangial
cells [15,89]. These mediators in turn activate podocytes and tubular epithelial cells to produce more pro-inflammatory cytokines
and chemokines, leading eventually to interstitial immune cell
infiltration, tubular injury and fibrosis. Therefore, IL-18 may induce
renal tissue damage by both immune and nonimmune-dependent
mechanisms [90]. Interestingly, inflammasome/IL-1b/IL-18 axis
has been recently reported to play a significant role in DNinduced tubulointerstitial lesions [91]. Vilaysane and colleagues
showed that targeting NLRP3 inflammasome or its downstream
effectors; IL-1b and IL-18 may be useful in the treatment of chronic
kidney diseases [92]. In diabetic animal models, circulating IL-1b
and IL-18 as well as renal expression of Nlrp3 were significantly
elevated followed by renal dysfunction. In addition, pharmacological and molecular targeting of inflammasome/IL-1b/IL-18 axis was
protective against DN [9395], suggesting this axis to play a fundamental role in the pathogenesis of DN. A summary of reports that
examined IL-18 in relation to various renal cells under diabetes
were illustrated in Table 2.

Caspase 1 is unique among the caspases family due to its ability


to activate both IL-1b and IL-18. Caspase-1 inhibitors are capable of
preventing the release of active IL-1b and IL-18. Therefore, the
inhibitors may have clinical benefit by reducing the activities of
both cytokines [107].
IL-1F7 is a member of IL-1 family which can negatively regulate
IL-18 activity. It acts by binding to IL-18BP to form a complex that
in turn prevents the functional complex formation between IL-18
and its receptor chains [108].
A naturally occurring IL-18 binding protein (IL-18BP) was discovered in 1999 during the search for extracellular receptors for
IL-18 in human urine samples. IL-18BP is constitutively secreted
protein that can effectively neutralize IL-18 activity. IL-18BP acts
through binding to the receptor-binding site of IL-18 with highaffinity (400 pmol/L) [109]. It is a 38-kDa soluble protein that exhibits some sequence homology with IL-18Ra [110]. In addition to
IL-18, IL-18BP can also bind to IL-37, augmenting the ability of
IL-18BP to deactivate IFN-c by IL-18 [108]. IL-18BP is currently
used in some clinical trials for treatment of rheumatoid arthritis
and severe psoriasis [75,111]. A study on type 2 diabetic patients
revealed that serum IL-18BP increased after IL-18 reached threshold and kidney injury developed, suggesting IL-18BP as a marker
for glomerular dysfunction [112]. Targeting IL-18 resulted in
decreased immune cell infiltration and protection of renal function
in different models of kidney diseases such as renal ischemia
reperfusion injury [113] glomerulonephritis [81] and renal fibrosis
[114]. However, to date targeting IL-18 in DN model has not been
fully investigated. Therefore, further studies are required to assess
the therapeutic intervention of IL-18 in DN.

5. Therapeutic strategies for reducing interleukin 18 activities

6. Conclusions

The biologic activity of IL-18 is regulated by the formation of


active form of the cytokine. In addition, other molecules including
soluble IL-18R, caspase-1, 18BP and other cytokines such as IL-12
and IL-15 are involved. The strategies for modulating IL-18 activity
include monoclonal antibodies to IL-18, caspase-1 inhibitors and
IL-18 receptor blockers [104].
IL-18Ra (IL-18Ra type II) is thought to be a decoy receptor lacking the TIR domain [105], while soluble form of IL-18Rb (small
truncated IL-18Rb) is proposed by stabilizing binding of IL-18 to
IL-18Ra with inhibition of downstream signaling [106]. Therefore,
these two isoforms are proposed to down-regulate IL-18 action.

Growing evidence indicates that activation of innate immunity


associated with the expansion of chronic inflammatory response is
a known factor in the pathogenesis of diabetic nephropathy. Diabetic kidney triggered metabolism and hemodynamics changes
that leads to activation of numerous inflammatory molecules.
The concept of inflammatory nature of diabetic nephropathy is
very important therapeutic perspective. It has been found that,
IL-18 is constitutively expressed in renal tubular epithelia, serum
and urine both in vivo and in vitro studies of diabetic nephropathy.
The increasing knowledge and understanding of the role of IL-18
inflammatory mechanisms will facilitate the development of new

20

N.M. Elsherbiny, M.M.H. Al-Gayyar / Cytokine 81 (2016) 1522

and effective therapeutic targets and strategies for preventing and


for halting the progression of diabetic nephropathy.
Conflict of interest
Al-Gayyar and Elsherbiny disclose that they do not have any
commercial association that might pose a conflict of interest in
connection with the manuscript.
References
[1] S. Yamagishi, T. Imaizumi, Diabetic vascular complications: pathophysiology,
biochemical basis and potential therapeutic strategy, Curr. Pharm. Des. 11
(18) (2005) 22792299.
[2] R.J. Macisaac, E.I. Ekinci, G. Jerums, Markers of and risk factors for the
development and progression of diabetic kidney disease, Am. J. Kidney Dis. 63
(Suppl. 2) (2014) S39S62.
[3] T.K. Ali, S. Matragoon, B.A. Pillai, G.I. Liou, A.B. El-Remessy, Peroxynitrite
mediates retinal neurodegeneration by inhibiting nerve growth factor
survival signaling in experimental and human diabetes, Diabetes 57 (4)
(2008) 889898.
[4] M.M. Al-Gayyar, S. Matragoon, B.A. Pillai, T.K. Ali, M.A. Abdelsaid, A.B. ElRemessy, Epicatechin blocks pro-nerve growth factor (proNGF)-mediated
retinal neurodegeneration via inhibition of p75 neurotrophin receptor
expression in a rat model of diabetes, Diabetologia 54 (3) (2011) 669680
(corrected).
[5] T.K. Ali, M.M. Al-Gayyar, S. Matragoon, B.A. Pillai, M.A. Abdelsaid, J.J.
Nussbaum, A.B. El-Remessy, Diabetes-induced peroxynitrite impairs the
balance of pro-nerve growth factor and nerve growth factor, and causes
neurovascular injury, Diabetologia 54 (3) (2011) 657668.
[6] N.M. Elsherbiny, M. Naime, S. Ahmad, A.M. Elsherbini, S. Mohammad, S.
Fulzele, A.B. El-Remessy, M.M. Al-Gayyar, L.A. Eissa, M.M. El-Shishtawy, G.
Han, R. White, T.F. Haroldo, G.I. Liou, Potential roles of adenosine deaminase2 in diabetic retinopathy, Biochem. Biophys. Res. Commun. (2013).
[7] A. Lim, Diabetic nephropathy complications and treatment, Int. J. Nephrol.
Renovasc. Dis. (2014) 73617381.
[8] N.M. Elsherbiny, M.M. Al-Gayyar, Adenosine receptors: new therapeutic
targets for inflammation in diabetic nephropathy, Inflamm. Allergy Drug
Targets (2013).
[9] R.M. Montero, A. Covic, L. Gnudi, D. Goldsmith, Diabetic nephropathy: what
does the future hold?, Int Urol. Nephrol. (2015).
[10] Y.S. Kanwar, J. Wada, L. Sun, P. Xie, E.I. Wallner, S. Chen, S. Chugh, F.R. Danesh,
Diabetic nephropathy: mechanisms of renal disease progression, Exp. Biol.
Med. (Maywood) 233 (1) (2008) 411.
[11] M. Dunlop, Aldose reductase and the role of the polyol pathway in diabetic
nephropathy, Kidney Int. Suppl. (2000) S3S12.
[12] H. Noh, G.L. King, The role of protein kinase C activation in diabetic
nephropathy, Kidney Int. Suppl. 106 (2007) S4953.
[13] H. Ha, I.A. Hwang, J.H. Park, H.B. Lee, Role of reactive oxygen species in the
pathogenesis of diabetic nephropathy, Diabetes Res. Clin. Pract. 82 (Suppl. 1)
(2008) S42S45.
[14] T. Chawla, D. Sharma, A. Singh, Role of the renin angiotensin system in
diabetic nephropathy, World J. Diabetes 1 (5) (2010) 141145.
[15] B.F. Schrijvers, A.S. De Vriese, A. Flyvbjerg, From hyperglycemia to diabetic
kidney disease: the role of metabolic, hemodynamic, intracellular factors and
growth factors/cytokines, Endocr. Rev. 25 (6) (2004) 9711010.
[16] S. Prabhakar, J. Starnes, S. Shi, B. Lonis, R. Tran, Diabetic nephropathy is
associated with oxidative stress and decreased renal nitric oxide production,
J. Am. Soc. Nephrol. 18 (11) (2007) 29452952.
[17] J.F. Navarro-Gonzalez, C. Mora-Fernandez, M. Muros de Fuentes, J. GarciaPerez, Inflammatory molecules and pathways in the pathogenesis of diabetic
nephropathy, Nat. Rev. Nephrol. 7 (6) (2011) 327340.
[18] P. Luo, Y. Zhou, H.H. Chang, J. Zhang, T. Seki, C.Y. Wang, E.W. Inscho, M.H.
Wang, Glomerular 20-HETE, EETs, and TGF-beta1 in diabetic nephropathy,
Am. J. Physiol. Renal Physiol. 296 (3) (2009) F556F563.
[19] P.A. Kumar, F.C. Brosius 3rd, R.K. Menon, The glomerular podocyte as a target
of growth hormone action: implications for the pathogenesis of diabetic
nephropathy, Curr. Diabetes Rev. 7 (1) (2011) 5055.
[20] C.L. Lin, F.S. Wang, Y.C. Hsu, C.N. Chen, M.J. Tseng, M.A. Saleem, P.J. Chang, J.Y.
Wang, Modulation of notch-1 signaling alleviates vascular endothelial
growth factor-mediated diabetic nephropathy, Diabetes 59 (8) (2010)
19151925.
[21] H. Suzuki, I. Usui, I. Kato, T. Oya, Y. Kanatani, Y. Yamazaki, S. Fujisaka, S.
Senda, Y. Ishii, M. Urakaze, A. Mahmood, S. Takasawa, H. Okamoto, M.
Kobayashi, K. Tobe, M. Sasahara, Deletion of platelet-derived growth factor
receptor-beta improves diabetic nephropathy in Ca(2)(+)/calmodulindependent protein kinase IIalpha (Thr286Asp) transgenic mice,
Diabetologia 54 (11) (2011) 29532962.
[22] W.J. Ni, L.Q. Tang, W. Wei, Research progress in signalling pathway in diabetic
nephropathy, Diabetes Metab. Res. Rev. 31 (3) (2015) 221233.
[23] J. Wada, H. Makino, Inflammation and the pathogenesis of diabetic
nephropathy, Clin. Sci. (Lond.) 124 (3) (2013) 139152.

[24] K. Kanasaki, G. Taduri, D. Koya, Diabetic nephropathy: the role of


inflammation in fibroblast activation and kidney fibrosis, Front. Endocrinol.
(Lausanne) (2013) 47.
[25] B. Rodriguez-Iturbe, Y. Quiroz, A. Shahkarami, Z. Li, N.D. Vaziri,
Mycophenolate mofetil ameliorates nephropathy in the obese Zucker rat,
Kidney Int. 68 (3) (2005) 10411047.
[26] Y. Wu, J. Dong, L. Yuan, C. Liang, K. Ren, W. Zhang, F. Fang, J. Shen, Nephrin
and podocin loss is prevented by mycophenolate mofetil in early
experimental diabetic nephropathy, Cytokine 44 (1) (2008) 8591.
[27] S. Wittmann, C. Daniel, A. Stief, R. Vogelbacher, K. Amann, C. Hugo, Long-term
treatment of sirolimus but not cyclosporine ameliorates diabetic
nephropathy in the rat, Transplantation 87 (9) (2009) 12901299.
[28] A.K. Lim, G.H. Tesch, Inflammation in diabetic nephropathy, Mediat. Inflamm.
2012 (2012) 146154.
[29] M.B. Duran-Salgado, A.F. Rubio-Guerra, Diabetic nephropathy and
inflammation, World J. Diabetes 5 (3) (2014) 393398.
[30] A.S. Awad, G.R. Kinsey, K. Khutsishvili, T. Gao, W.K. Bolton, M.D. Okusa,
Monocyte/macrophage chemokine receptor CCR2 mediates diabetic renal
injury, Am. J. Physiol. Renal Physiol. 301 (6) (2011) F1358F1366.
[31] Y. Liu, Cellular and molecular mechanisms of renal fibrosis, Nat. Rev. Nephrol.
7 (12) (2011) 684696.
[32] R. Hojs, R. Ekart, S. Bevc, N. Hojs, Biomarkers of renal disease and progression
in patients with diabetes, J. Clin. Med. 4 (5) (2015) 10101024.
[33] S. Maeda, Do inflammatory cytokine genes confer susceptibility to diabetic
nephropathy?, Kidney Int 74 (4) (2008) 413415.
[34] J. Donate-Correa, E. Martin-Nunez, M. Muros-de-Fuentes, C. Mora-Fernandez,
J.F. Navarro-Gonzalez, Inflammatory cytokines in diabetic nephropathy, J.
Diabetes Res. 2015 (2015) 948417.
[35] D.A. Vesey, C. Cheung, L. Cuttle, Z. Endre, G. Gobe, D.W. Johnson, Interleukin1beta stimulates human renal fibroblast proliferation and matrix protein
production by means of a transforming growth factor-beta-dependent
mechanism, J. Lab. Clin. Med. 140 (5) (2002) 342350.
[36] S. Jones, S. Jones, A.O. Phillips, Regulation of renal proximal tubular epithelial
cell hyaluronan generation: implications for diabetic nephropathy, Kidney
Int. 59 (5) (2001) 17391749.
[37] M. Dalla Vestra, M. Mussap, P. Gallina, M. Bruseghin, A.M. Cernigoi, A. Saller,
M. Plebani, P. Fioretto, Acute-phase markers of inflammation and glomerular
structure in patients with type 2 diabetes, J. Am. Soc. Nephrol. 16 (Suppl. 1)
(2005) S78S82.
[38] D.L. Coleman, C. Ruef, Interleukin-6: an autocrine regulator of mesangial cell
growth, Kidney Int. 41 (3) (1992) 604606.
[39] J.J. Boyle, P.L. Weissberg, M.R. Bennett, Tumor necrosis factor-alpha promotes
macrophage-induced vascular smooth muscle cell apoptosis by direct and
autocrine mechanisms, Arterioscler. Thromb. Vasc. Biol. 23 (9) (2003) 1553
1558.
[40] N. Koike, T. Takamura, S. Kaneko, Induction of reactive oxygen species from
isolated rat glomeruli by protein kinase C activation and TNF-alpha
stimulation, and effects of a phosphodiesterase inhibitor, Life Sci. 80 (18)
(2007) 17211728.
[41] L. Sun, Y.S. Kanwar, Relevance of TNF-alpha in the context of other
inflammatory cytokines in the progression of diabetic nephropathy, Kidney
Int. 88 (4) (2015) 662665.
[42] T. Fujita, N. Ogihara, Y. Kamura, A. Satomura, Y. Fuke, C. Shimizu, Y. Wada, K.
Matsumoto, Interleukin-18 contributes more closely to the progression of
diabetic nephropathy than other diabetic complications, Acta Diabetol. 49 (2)
(2012) 111117.
[43] D.E. Smith, The biological paths of IL-1 family members IL-18 and IL-33, J.
Leukoc. Biol. 89 (3) (2011) 383392.
[44] K. Nakamura, H. Okamura, M. Wada, K. Nagata, T. Tamura, Endotoxin-induced
serum factor that stimulates gamma interferon production, Infect. Immun. 57
(2) (1989) 590595.
[45] H. Okamura, H. Tsutsi, T. Komatsu, M. Yutsudo, A. Hakura, T. Tanimoto, K.
Torigoe, T. Okura, Y. Nukada, K. Hattori, et al., Cloning of a new cytokine
that induces IFN-gamma production by T cells, Nature 378 (6552) (1995) 88
91.
[46] F. Martinon, J. Tschopp, Inflammatory caspases and inflammasomes: master
switches of inflammation, Cell Death Differ. 14 (1) (2007) 1022.
[47] K. Nakanishi, T. Yoshimoto, H. Tsutsui, H. Okamura, Interleukin-18 regulates
both Th1 and Th2 responses, Annu. Rev. Immunol. (2001) 1942319474.
[48] S.M. Krishnan, C.G. Sobey, E. Latz, A. Mansell, G.R. Drummond, IL-1 beta and
IL-18: inflammatory markers or mediators of hypertension?, Br J. Pharmacol.
171 (24) (2014) 55895602.
[49] S.K. Sedimbi, T. Hagglof, M.C. Karlsson, IL-18 in inflammatory and
autoimmune disease, Cell Mol. Life Sci. 70 (24) (2013) 47954808.
[50] N. Udagawa, N.J. Horwood, J. Elliott, A. Mackay, J. Owens, H. Okamura, M.
Kurimoto, T.J. Chambers, T.J. Martin, M.T. Gillespie, Interleukin-18
(interferon-gamma-inducing factor) is produced by osteoblasts and acts via
granulocyte/macrophage colony-stimulating factor and not via interferongamma to inhibit osteoclast formation, J. Exp. Med. 185 (6) (1997) 1005
1012.
[51] M. Cumberbatch, R.J. Dearman, C. Antonopoulos, R.W. Groves, I. Kimber,
Interleukin (IL)-18 induces Langerhans cell migration by a tumour necrosis
factor-alpha- and IL-1beta-dependent mechanism, Immunology 102 (3)
(2001) 323330.
[52] C.A. Dinarello, Interleukin-18 and the pathogenesis of inflammatory diseases,
Semin. Nephrol. 27 (1) (2007) 98114.

N.M. Elsherbiny, M.M.H. Al-Gayyar / Cytokine 81 (2016) 1522


[53] O.J. Harrison, N. Srinivasan, J. Pott, C. Schiering, T. Krausgruber, N.E. Ilott, K.J.
Maloy, Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3
(+) Treg cell function in the intestine, Mucosal Immunol. 8 (6) (2015) 1226
1236.
[54] N. Tsutsumi, T. Kimura, K. Arita, M. Ariyoshi, H. Ohnishi, T. Yamamoto, X. Zuo,
K. Maenaka, E.Y. Park, N. Kondo, M. Shirakawa, H. Tochio, Z. Kato, The
structural basis for receptor recognition of human interleukin-18, Nat.
Commun. (2014) 55340.
[55] C.A. Dinarello, Novel targets for interleukin 18 binding protein, Ann. Rheum.
Dis. 60 (Suppl. 3iii) (2001) 1824.
[56] S. Akira, K. Takeda, T. Kaisho, Toll-like receptors: critical proteins linking
innate and acquired immunity, Nat. Immunol. 2 (8) (2001) 675680.
[57] M. Banerjee, M. Saxena, Interleukin-1 (IL-1) family of cytokines: role in type 2
diabetes, Clin. Chim. Acta 413 (1516) (2012) 11631170.
[58] C. Gabay, I.B. McInnes, The biological and clinical importance of the new
generation cytokines in rheumatic diseases, Arthritis Res. Ther. 11 (3) (2009)
230.
[59] W.P. Arend, G. Palmer, C. Gabay, IL-1, IL-18, and IL-33 families of cytokines,
Immunol. Rev. (2008) 2232022338.
[60] H.P. Carroll, V. Paunovic, M. Gadina, Signalling, inflammation and arthritis:
crossed signals: the role of interleukin-15 and -18 in autoimmunity,
Rheumatology (Oxford) 47 (9) (2008) 12691277.
[61] C.A. Dinarello, G. Fantuzzi, Interleukin-18 and host defense against infection,
J. Infect. Dis. 187 (Suppl. 2) (2003) S370S384.
[62] S. Alboni, D. Cervia, S. Sugama, B. Conti, Interleukin 18 in the CNS, J.
Neuroinflamm. 79 (2010).
[63] H. Tsutsui, K. Nakanishi, K. Matsui, K. Higashino, H. Okamura, Y. Miyazawa, K.
Kaneda, IFN-gamma-inducing factor up-regulates Fas ligand-mediated
cytotoxic activity of murine natural killer cell clones, J. Immunol. 157 (9)
(1996) 39673973.
[64] T.A. Fehniger, M.H. Shah, M.J. Turner, J.B. VanDeusen, S.P. Whitman, M.A.
Cooper, K. Suzuki, M. Wechser, F. Goodsaid, M.A. Caligiuri, Differential
cytokine and chemokine gene expression by human NK cells following
activation with IL-18 or IL-15 in combination with IL-12: implications for the
innate immune response, J. Immunol. 162 (8) (1999) 45114520.
[65] C.F. Fortin, T. Ear, P.P. McDonald, Autocrine role of endogenous interleukin-18
on inflammatory cytokine generation by human neutrophils, FASEB J. 23 (1)
(2009) 194203.
[66] J.K. Lee, S.H. Kim, E.C. Lewis, T. Azam, L.L. Reznikov, C.A. Dinarello, Differences
in signaling pathways by IL-1beta and IL-18, Proc. Natl. Acad. Sci. USA 101
(23) (2004) 88158820.
[67] T. Skurk, H. Kolb, S. Muller-Scholze, K. Rohrig, H. Hauner, C. Herder, The
proatherogenic cytokine interleukin-18 is secreted by human adipocytes, Eur.
J. Endocrinol. 152 (6) (2005) 863868.
[68] L.E. Harrington, P.R. Mangan, C.T. Weaver, Expanding the effector CD4 T-cell
repertoire: the Th17 lineage, Curr. Opin. Immunol. 18 (3) (2006) 349356.
[69] T. Yoshimoto, H. Tsutsui, K. Tominaga, K. Hoshino, H. Okamura, S. Akira, W.E.
Paul, K. Nakanishi, IL-18, although antiallergic when administered with IL-12,
stimulates IL-4 and histamine release by basophils, Proc. Natl. Acad. Sci. USA
96 (24) (1999) 1396213966.
[70] H. Okamura, H. Tsutsui, S. Kashiwamura, T. Yoshimoto, K. Nakanishi,
Interleukin-18: a novel cytokine that augments both innate and acquired
immunity, Adv. Immunol. (1998) 7028170312.
[71] J.C. Morel, C.C. Park, P. Kumar, A.E. Koch, Interleukin-18 induces rheumatoid
arthritis synovial fibroblast CXC chemokine production through NFkappaB
activation, Lab. Invest. 81 (10) (2001) 13711383.
[72] C.C. Wu, H.K. Sytwu, Y.F. Lin, Cytokines in diabetic nephropathy, Adv. Clin.
Chem. (2012) 56555674.
[73] J.C. Morel, C.C. Park, J.M. Woods, A.E. Koch, A novel role for interleukin-18 in
adhesion molecule induction through NF kappa B and phosphatidylinositol
(PI) 3-kinase-dependent signal transduction pathways, J. Biol. Chem. 276 (40)
(2001) 3706937075.
[74] N. Gerdes, G.K. Sukhova, P. Libby, R.S. Reynolds, J.L. Young, U. Schonbeck,
Expression of interleukin (IL)-18 and functional IL-18 receptor on human
vascular endothelial cells, smooth muscle cells, and macrophages:
implications for atherogenesis, J. Exp. Med. 195 (2) (2002) 245257.
[75] C.A. Dinarello, Interleukin 1 and interleukin 18 as mediators of inflammation
and the aging process, Am. J. Clin. Nutr. 83 (2) (2006) 447S455S.
[76] V.Y. Melnikov, T. Ecder, G. Fantuzzi, B. Siegmund, M.S. Lucia, C.A. Dinarello, R.
W. Schrier, C.L. Edelstein, Impaired IL-18 processing protects caspase-1deficient mice from ischemic acute renal failure, J. Clin. Invest. 107 (9) (2001)
11451152.
[77] V.Y. Melnikov, S. Faubel, B. Siegmund, M.S. Lucia, D. Ljubanovic, C.L. Edelstein,
Neutrophil-independent mechanisms of caspase-1- and IL-18-mediated
ischemic acute tubular necrosis in mice, J. Clin. Invest. 110 (8) (2002)
10831091.
[78] H. Wu, M.L. Craft, P. Wang, K.R. Wyburn, G. Chen, J. Ma, B. Hambly, S.J.
Chadban, IL-18 contributes to renal damage after ischemiareperfusion, J.
Am. Soc. Nephrol. 19 (12) (2008) 23312341.
[79] J. Menke, T. Bork, B. Kutska, K.T. Byrne, M. Blanfeld, M. Relle, V.R. Kelley, A.
Schwarting, Targeting transcription factor Stat4 uncovers a role for
interleukin-18 in the pathogenesis of severe lupus nephritis in mice,
Kidney Int. 79 (4) (2011) 452463.
[80] K.R. Wyburn, S.J. Chadban, T. Kwan, S.I. Alexander, H. Wu, Interleukin-18
binding protein therapy is protective in adriamycin nephropathy, Am. J.
Physiol. Renal Physiol. 304 (1) (2013) F68F76.

21

[81] M. Sugiyama, K. Kinoshita, K. Kishimoto, H. Shimazu, Y. Nozaki, S. Ikoma, M.


Funauchi, Deletion of IL-18 receptor ameliorates renal injury in bovine serum
albumin-induced glomerulonephritis, Clin. Immunol. 128 (1) (2008) 103
108.
[82] J. Faust, J. Menke, J. Kriegsmann, V.R. Kelley, W.J. Mayet, P.R. Galle, A.
Schwarting, Correlation of renal tubular epithelial cell-derived interleukin-18
up-regulation with disease activity in MRL-Faslpr mice with autoimmune
lupus nephritis, Arthritis Rheum. 46 (11) (2002) 30833095.
[83] Y. Moriwaki, T. Yamamoto, Y. Shibutani, E. Aoki, Z. Tsutsumi, S. Takahashi, H.
Okamura, M. Koga, M. Fukuchi, T. Hada, Elevated levels of interleukin-18 and
tumor necrosis factor-alpha in serum of patients with type 2 diabetes
mellitus: relationship with diabetic nephropathy, Metabolism 52 (5) (2003)
605608.
[84] A. Nakamura, K. Shikata, M. Hiramatsu, T. Nakatou, T. Kitamura, J. Wada, T.
Itoshima, H. Makino, Serum interleukin-18 levels are associated with
nephropathy and atherosclerosis in Japanese patients with type 2 diabetes,
Diabetes Care 28 (12) (2005) 28902895.
[85] K. Miyauchi, Y. Takiyama, J. Honjyo, M. Tateno, M. Haneda, Upregulated IL-18
expression in type 2 diabetic subjects with nephropathy: TGF-beta1
enhanced IL-18 expression in human renal proximal tubular epithelial cells,
Diabetes Res. Clin. Pract. 83 (2) (2009) 190199.
[86] S. Gangemi, A. Mallamace, P.L. Minciullo, D. Santoro, R.A. Merendino, V.
Savica, G. Bellinghieri, Involvement of interleukin-18 in patients on
maintenance haemodialysis, Am. J. Nephrol. 22 (56) (2002) 417421.
[87] C.K. Chiang, S.P. Hsu, M.F. Pai, Y.S. Peng, T.I. Ho, S.H. Liu, K.Y. Hung, T.J. Tsai, B.
S. Hsieh, Plasma interleukin-18 levels in chronic renal failure and continuous
ambulatory peritoneal dialysis, Blood Purif. 23 (2) (2005) 144148.
[88] M. Girndt, U. Sester, H. Kaul, H. Kohler, Production of proinflammatory and
regulatory monokines in hemodialysis patients shown at a single-cell level, J.
Am. Soc. Nephrol. 9 (9) (1998) 16891696.
[89] J.F. Navarro-Gonzalez, C. Mora-Fernandez, The role of inflammatory cytokines
in diabetic nephropathy, J. Am. Soc. Nephrol. 19 (3) (2008) 433442.
[90] B. Shi, Z. Ni, L. Cao, M. Zhou, S. Mou, Q. Wang, M. Zhang, W. Fang, Y. Yan, J.
Qian, Serum IL-18 is closely associated with renal tubulointerstitial injury
and predicts renal prognosis in IgA nephropathy, Mediat. Inflamm. 2012
(2012) 728417.
[91] C.M. Turner, N. Arulkumaran, M. Singer, R.J. Unwin, F.W. Tam, Is the
inflammasome a potential therapeutic target in renal disease?, BMC
Nephrol 1521 (2014).
[92] A. Vilaysane, J. Chun, M.E. Seamone, W. Wang, R. Chin, S. Hirota, Y. Li, S.A.
Clark, J. Tschopp, K. Trpkov, B.R. Hemmelgarn, P.L. Beck, D.A. Muruve, The
NLRP3 inflammasome promotes renal inflammation and contributes to CKD,
J. Am. Soc. Nephrol. 21 (10) (2010) 17321744.
[93] C. Wang, Y. Pan, Q.Y. Zhang, F.M. Wang, L.D. Kong, Quercetin and allopurinol
ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3
inflammasome activation and lipid accumulation, PLoS ONE 7 (6) (2012)
e38285.
[94] A. Solini, S. Menini, C. Rossi, C. Ricci, E. Santini, C. Blasetti Fantauzzi, C.
Iacobini, G. Pugliese, The purinergic 2X7 receptor participates in renal
inflammation and injury induced by high-fat diet: possible role of NLRP3
inflammasome activation, J. Pathol. 231 (3) (2013) 342353.
[95] K. Shahzad, F. Bock, W. Dong, H. Wang, S. Kopf, S. Kohli, M.M. Al-Dabet, S.
Ranjan, J. Wolter, C. Wacker, R. Biemann, S. Stoyanov, K. Reymann, P.
Soderkvist, O. Gross, V. Schwenger, S. Pahernik, P.P. Nawroth, H.J. Grone, T.
Madhusudhan, B. Isermann, Nlrp3-inflammasome activation in non-myeloidderived cells aggravates diabetic nephropathy, Kidney Int. 87 (1) (2015) 74
84.
[96] R.A. Mahmoud, S.A. El-Ezz, A.S. Hegazy, Increased serum levels of interleukin18 in patients with diabetic nephropathy, Ital. J. Biochem. 53 (2) (2004) 73
81.
[97] S. Araki, M. Haneda, D. Koya, T. Sugimoto, K. Isshiki, M. Chin-Kanasaki, T. Uzu,
A. Kashiwagi, Predictive impact of elevated serum level of IL-18 for early
renal dysfunction in type 2 diabetes: an observational follow-up study,
Diabetologia 50 (4) (2007) 867873.
[98] A.E. Altinova, I. Yetkin, E. Akbay, N. Bukan, M. Arslan, Serum IL-18 levels in
patients with type 1 diabetes: relations to metabolic control and
microvascular complications, Cytokine 42 (2) (2008) 217221.
[99] S.S. Kim, S.H. Song, I.J. Kim, J.Y. Yang, J.G. Lee, I.S. Kwak, Y.K. Kim, Clinical
implication of urinary tubular markers in the early stage of nephropathy with
type 2 diabetic patients, Diabetes Res. Clin. Pract. 97 (2) (2012) 251257.
[100] N.M. Elsherbiny, K.H. Abd El Galil, M.M. Gabr, M.M. Al-Gayyar, L.A. Eissa, M.
M. El-Shishtawy, Reno-protective effect of NECA in diabetic nephropathy:
implication of IL-18 and ICAM-1, Eur. Cytokine Netw. 23 (3) (2012) 7886.
[101] M.D. Sanchez-Nino, M. Bozic, E. Cordoba-Lanus, P. Valcheva, O. Gracia, M.
Ibarz, E. Fernandez, J.F. Navarro-Gonzalez, A. Ortiz, J.M. Valdivielso, Beyond
proteinuria: VDR activation reduces renal inflammation in experimental
diabetic nephropathy, Am. J. Physiol. Renal Physiol. 302 (6) (2012) F647
F657.
[102] N.M. Elsherbiny, M.M. Al-Gayyar, K.H. Abd El-Galil, Nephroprotective role of
dipyridamole in diabetic nephropathy: Effect on inflammation and apoptosis,
Life Sci. 143 (2015) 817.
[103] C. Luo, T. Li, C. Zhang, Q. Chen, Z. Li, J. Liu, Y. Wang, Therapeutic effect of
alprostadil in diabetic nephropathy: possible roles of angiopoietin-2 and IL18, Cell Physiol. Biochem. 34 (3) (2014) 916928.
[104] C.A. Dinarello, G. Kaplanski, Interleukin-18 treatment options for
inflammatory diseases, Exp. Rev. Clin. Immunol. 1 (4) (2005) 619632.

22

N.M. Elsherbiny, M.M.H. Al-Gayyar / Cytokine 81 (2016) 1522

[105] S. Alboni, D. Cervia, B. Ross, C. Montanari, A.S. Gonzalez, M. Sanchez-Alavez,


M.C. Marcondes, D. De Vries, S. Sugama, N. Brunello, J. Blom, F. Tascedda, B.
Conti, Mapping of the full length and the truncated interleukin-18 receptor
alpha in the mouse brain, J. Neuroimmunol. 214 (12) (2009) 4354.
[106] D. Fiszer, N. Rozwadowska, L. Rychlewski, W. Kosicki, M. Kurpisz,
Identification of IL-18RAP mRNA truncated splice variants in human testis
and the other human tissues, Cytokine 39 (3) (2007) 178183.
[107] X.Q. Ma, H.J. Zhang, Y.H. Zhang, Y.H. Chen, F. Wu, J.Q. Du, H.P. Yu, Z.L. Zhou, J.
Y. Li, F.J. Nan, J. Li, Novel irreversible caspase-1 inhibitor attenuates the
maturation of intracellular interleukin-1 beta, Biochem. Cell Biol. 85 (1)
(2007) 5665.
[108] P. Bufler, T. Azam, F. Gamboni-Robertson, L.L. Reznikov, S. Kumar, C.A.
Dinarello, S.H. Kim, A complex of the IL-1 homologue IL-1F7b and IL-18binding protein reduces IL-18 activity, Proc. Natl. Acad. Sci. USA 99 (21)
(2002) 1372313728.
[109] N.N. Shan, X.J. Zhu, J. Peng, P. Qin, X.W. Zhuang, H.C. Wang, M. Hou,
Interleukin 18 and interleukin 18 binding protein in patients with idiopathic
thrombocytopenic purpura, Br. J. Haematol. 144 (5) (2009) 755761.

[110] D. Novick, S.H. Kim, G. Fantuzzi, L.L. Reznikov, C.A. Dinarello, M. Rubinstein,
Interleukin-18 binding protein: a novel modulator of the Th1 cytokine
response, Immunity 10 (1) (1999) 127136.
[111] H. Marotte, S. Ahmed, J.H. Ruth, A.E. Koch, Blocking ERK-1/2 reduces tumor
necrosis factor alpha-induced interleukin-18 bioactivity in rheumatoid
arthritis synovial fibroblasts by induction of interleukin-18 binding protein
A, Arthritis Rheum. 62 (3) (2010) 722731.
[112] T. Fujita, C. Shimizu, Y. Fuke, A. Satomura, M. Abe, K. Kaizu, K. Matsumoto, M.
Soma, Serum interleukin-18 binding protein increases with behavior
different from IL-18 in patients with diabetic nephropathy, Diabetes Res.
Clin. Pract. 92 (3) (2011) e66e69.
[113] J. Wang, Q. Long, W. Zhang, N. Chen, Protective effects of exogenous
interleukin 18-binding protein in a rat model of acute renal ischemia
reperfusion injury, Shock 37 (3) (2012) 333340.
[114] A.H. Bani-Hani, J.A. Leslie, H. Asanuma, C.A. Dinarello, M.T. Campbell, D.R.
Meldrum, H. Zhang, K. Hile, K.K. Meldrum, IL-18 neutralization ameliorates
obstruction-induced epithelial-mesenchymal transition and renal fibrosis,
Kidney Int. 76 (5) (2009) 500511.