Beruflich Dokumente
Kultur Dokumente
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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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
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]
[14]
Intracellular factors
[17]
[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.
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
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.
19
Summary
Cell type
References
Human
Serum
[96]
[85]
Serum
[83,84,97,98]
Urine
[99]
[93,100102]
[103]
[94]
Diabetic rodents
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.
6. Conclusions
20
21
22
[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.