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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 Department of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egyptb 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 uri-

nary 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 con-

tributing factor to the pathogenesis of diabetic nephropathy. Meanwhile, IL-18, a member of the IL-1 fam-

ily 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 pro-

vide imperfect protection against renal progression. This imperfection points to the need for newer ther-

apeutic 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. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

2. Diabetic nephropathy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

2.1. Diabetic nephropathy and inflammation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

3. IL-18 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

3.1. Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

3.2. Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

3.3. Signaling pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

3.4. Biological functions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

4. IL-18 in diabetic nephropathy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

5. Therapeutic strategies for reducing interleukin 18 activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

6. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

1. Introduction

Considered as a leading reason for end-stage renal failure, dia-

betic 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

http://dx.doi.org/10.1016/j.cyto.2016.01.014

1043-4666/ 2016 Elsevier Ltd. All rights reserved.

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

intracellular adhesion molecule-1; IL-18BP, IL-18 binding protein; IRAKs, IL-1R-

associated 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).

Cytokine 81 (2016) 1522

Contents lists available at ScienceDirect

Cytokine

j o u r n a l h o m e p a g e : w w w . j o u r n a l s . e l s e v i e r . c o m / c y t o k i n e

http://dx.doi.org/10.1016/j.cyto.2016.01.014mailto:mhgayyar@yahoo.comhttp://dx.doi.org/10.1016/j.cyto.2016.01.014http://www.sciencedirect.com/science/journal/10434666http://www.journals.elsevier.com/cytokinehttp://www.journals.elsevier.com/cytokinehttp://www.sciencedirect.com/science/journal/10434666http://dx.doi.org/10.1016/j.cyto.2016.01.014mailto:mhgayyar@yahoo.comhttp://dx.doi.org/10.1016/j.cyto.2016.01.014http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://crossmark.crossref.org/dialog/?doi=10.1016/j.cyto.2016.01.014&domain=pdfhttp://-/?-http://-/?-

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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 progres-

sive 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 fail-

ure[7]. DN remains the most prevalent chronic disease of the kid-

ney. 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. Sustainedhyperglycemia and hypertension are the most important factors

in the initiation and progression of nephropathy. Some of these

mechanisms were summarized inTable 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 angiotensin-

receptor 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 andinflammation 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

factorjB (NFjB) are all implicated in processes related to diabeticnephropathy [23]. Inflammation plays vital role in the process of

fibroblast activation and subsequent tissue fibrosis; the most fun-

damental and distinguished feature of DN. Therefore, inflamma-

tory 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 renalinjury comes from studies where the use of immunosuppressive

strategies declined the accumulation of renal macrophage leading

to attenuation of the development of DN [2527].

Hyperglycemia, advanced glycation products and other compo-

nents of diabetic milieu induce activation of renal cells, which lead

to expression of numerous compounds such as chemokines, adhe-sion 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 base-

ment 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 kid-

ney has been proved to protect against renal injury in animal mod-

els 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 cytoki-

nes that have been reported to play a pivotal role in the pathogen-

esis 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 polymor-

phism of both the pro-inflammatory cytokines and their receptors

can be used as strong predictor of the susceptibility and progres-

sion of DN[33]. Indeed, targeting cytokines and/or their receptors

ameliorated DN, implying significance of cytokines as key playersinvolved in DN pathophysiology [34].

Table 1

Causes of diabetic nephropathy.

Factors causing diabetic

nephropathy

Reference

Metabolic factors Advanced glycation end products [10]

Aldose reductase/polyol pathway [11]

Diacylglycerol (DAG)-protein kinase

C (PKC) pathway

[12]

Reactive oxygen species [13]

Hemodynamic factors Activation of rennin angiotensin

system

[14]

Endothelin [15]

Nitric oxide [16]

Intracellular factors Nuclear factor-kB (NF-KB) [17]

Growth factors and

cytokines

Transforming growth factor-b [18]

Growth hormone and insulin like

growth factor

[19]

Vascular endothelial growth factor [20]

Platelet derived growth factor [21]

Diabec

renal injury

Hemodynamic

abnormalies Metabolic

derangements

Hormones

Systemic and

intraglomerular

hypertension Mechanical

strain

Altered

shear

stress

Advanced

glycaon

end products

Hyperglycemia

Hyperlipidemia

Angiotensin II

Sex hormone

Growth

hormone

SmokingObesity

Dietary

factors

External noxious or

proinflammatory factors

Fig. 1. Factors associated with diabetic renal injury that induced the activation of

diverse signal transduction systems in kidney cells.

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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 elevat-

ing 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 base-

ment membrane thickening[37]. In addition, it alters endothelial

permeability and mesangial cell expansion [38]. TNF-a causesdirect 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 cytoki-

nes, 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 dam-

ages kidney cells as well as it activates production of other inflam-

matory cytokines, such as IL-1, interferon c and TNF[42]. Despitethe large literature on the role of IL-18 in the pathogenesis of dif-

ferent kidney diseases, studies need to determine whether IL-18 is

a suitable target for therapeutic intervention to ameliorate the pro-

gression of DN.

3. IL-18

IL-18 is a member of the IL-1 family of cytokines. It exhibits sig-

nificant sequence homology with both IL-33 and IL-1b[43]. It was

first described in 1989 as an IFN-c-inducing factor in the circula-tion of mice following endotoxin injection [44]. With the molecular

cloning of IFN-c-inducing factor in 1995, the name was changed toIL-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 acti-

vated. 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, vascularsmooth 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 molecu-

lar 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 twoa-helices (a1a2)[54]. In this regard, IL-18 shows struc-tural similarity to IL-1b and IL-33 [43]. The IL-18 structure is

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 asIL-1Rrp1, IL-18R1 or IL-1R5) which is a ligand-binding chain and

a coreceptor termed IL-18Rb chain (also called IL-18RacP, IL-

18RII or IL-1R7); both chains have three amino terminal extracel-

lular Ig-like domains and one intracellular carboxy-terminal region

which have Toll/IL-1 receptor (TIR) domain [57]. The a chain isresponsible 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. Bindingof IL-18 toa chain leads to recruitment of the non-binding IL18Rbchain, 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 activatethe 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 com-

plex. First, IL-18 binds to the low affinity (about 10 nM) IL-18Rachain 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-1R-

associated kinases (IRAKs) followed by interaction with TNF recep-tor 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 NFkB-

inducing 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 forgene transcription. The signaling pathway of IL-18 was summa-

rized 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 collabo-

ration with other cytokines to regulate the immune system

responses. IL-18 amplifies IFN-c production in synergy with otherTh1-related cytokines, IL-2, IL-15, IL-12 and IL-23. In addition, IL-

18 stimulates natural killer (NK) cell maturation alone or in combi-

nation with IL15[63]. Indeed, it was found that IL-18, in concert

with IL-12 and IL-15 consolidates the production of TNF-a, GM-CSF, and the chemokines CCL3 and CCL4 by NK cells [64]. More-

over, 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 ofmonocytes [61,65]. Further, IL-18 enhances cytokines-mediated

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activation of T cells and macrophages through enhancing cellcell

interactions between both types of cells [66]. InCD4+ 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 IL-

2. 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, IL-

18, in conjunction with IL-3, induces the production of IL-4 and IL-13 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 andmesenchymal 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 inexperimental 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 tomacrophage 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 dis-

ease models [76,82]. In diabetic patients, the serum and urinary

concentrations of IL-18 have been reported to be significantly ele-

vated with an independent association with urinary albumin

excretion and b-2 microglobulin [83,84]. Moreover, in a prospec-

tive investigation, IL-18 accumulation in both serum and urine

were directly associated with the UAE as well as with alterationin albuminuria during the follow-up period[84]. The independent

IL-18

TRAF6

MAPK

MyD88

IL-1

8R

IL-1

8R

IL-18R

NFB

genetranscription

apoptoticpathway

Pro-IL-18Caspase-1

IRAKs

Fig. 2. Signalingpathway 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.

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

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correlation of IL-18 with clinical markers of glomerular and tubu-lointerstitial 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 dys-

function 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 dis-

eases, 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 produc-

tion of pro-inflammatory cytokines and chemokines by mesangial

cells [15,89]. These mediators in turn activate podocytes and tubu-

lar epithelial cells to produce more pro-inflammatory cytokines

and chemokines, leading eventually to interstitial immune cellinfiltration, 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 DN-

induced 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, pharmacolog-

ical and molecular targeting of inflammasome/IL-1b/IL-18 axis was

protective against DN [9395], suggesting this axis to play a funda-

mental role in the pathogenesis of DN. A summary of reports that

examined IL-18 in relation to various renal cells under diabeteswere illustrated inTable 2.

5. Therapeutic strategies for reducing interleukin 18 activities

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 lack-ing 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.

Caspase 1 is unique among the caspases family due to its abilityto 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 dis-

covered 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 high-

affinity (400 pmol/L) [109]. It is a 38-kDa soluble protein that exhi-bits some sequence homology with IL-18Ra [110]. In addition toIL-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 currentlyused 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 thresh-

old 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.

6. Conclusions

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. Dia-

betic 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 bothin vivoandin vitro studies of diabetic nephropathy.

The increasing knowledge and understanding of the role of IL-18inflammatory mechanisms will facilitate the development of new

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

Serum [96]

IL-18 was overexpressed in human tubular epithelial cells in

diabetic nephropathy through activation of MAPK pathways

induced by TGF-b1

Tubular epithelial cells [85]

Elevated serum and urinary IL-18 in patients with type 2 diabetescompared with healthy controls. There is a positive correlation

between IL-18 levels in diabetic patients and the development of

urinary albumin excretion

Serum [83,84,97,98]

Urinary IL-18 is associated with albuminuria in the early stage of

nephropathy in type 2 diabetics and may reflect inflammatory

processing

Urine [99]

Diabetic rodents Diabetic nephropathy is associated with elevated protein and

gene expression of IL-18

Rat renal tissue [93,100102]

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

Mouse renal tissue/mouse

glomerular endothelial cells

[103]

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

Mouse renal tissue/mouse podocytes [94]

N.M. Elsherbiny, M.M.H. Al-Gayyar / Cytokine 81 (2016) 1522 19

http://-/?-http://-/?-

7/26/2019 1-s2.0-S104346661630014xxX-main

6/8

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.

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