Signaling through the interleukin-18 receptor α attenuates inflammation in cisplatin-induced acute kidney injury

Interleukin (IL)-18 is produced by leukocytes and renal parenchymal cells (tubular epithelial cells, podocytes, and mesangial cells). The IL-18 receptor (IL-18R) is expressed on these cells in cisplatin-induced acute kidney injury, but the role of IL-18R is unknown. To help define this, we compared IL-18Rα knockout with wild-type mice in cisplatin-induced acute kidney injury and found deteriorated kidney function, tubular damage, increased accumulation of leukocytes (CD4(+) and CD8(+) T-cells, macrophages, and neutrophils), upregulation of early kidney injury biomarkers (serum TNF, urinary IL-18, and KIM-1 levels), and increased expression of pro-inflammatory molecules downstream of IL-18. In vitro, leukocytes from the spleen and kidneys of the knockout mice produced greater amounts of pro-inflammatory cytokines upon stimulation with concanavalin A compared to that in wild-type mice. Levels of the suppressor of cytokine signaling 1 and 3 (negative regulators of cytokine signaling) were reduced in the spleen and kidneys of IL-18Rα-deficient compared to wild-type mice. Adoptive transfer of wild-type splenocytes by IL-18Rα-deficient mice led to decreased cisplatin nephrotoxicity compared to control IL-18Rα-deficient mice. In contrast, anti-IL-18Rα and anti-IL-18Rβ antibody treatment tended to increase cisplatin nephrotoxicity in wild-type mice. Thus, signaling through IL-18Rα activates both inflammation-suppressing and pro-injury pathways in cisplatin-induced acute kidney injury.     

Proximal tubules from caspase-1-deficient mice are protected against hypoxia-induced membrane injury.

BACKGROUND: Caspase-1 is a proinflammatory caspase via activation of the cytokine IL-18. We have recently demonstrated that the caspase-1-mediated production of IL-18 plays a deleterious role in ischaemic acute renal failure (ARF) which is independent of neutrophils and CD4+ T cells. The role of caspase-1 in hypoxia-induced membrane injury of proximal tubules (PT) in vitro is unknown. METHODS: Freshly isolated mouse PT exposed to 25 min of hypoxia were used to study the role of caspases, caspase-1 and IL-18 in hypoxia-induced membrane injury. Lactate dehydrogenase (LDH) release into the PT medium was used as a biochemical parameter of cell membrane damage. IL-18 was determined by enzyme-linked immunosorbent assay (ELISA) and immunoblotting. RESULTS: PT pre-incubated with the novel pancaspase inhibitor IDN-8050 were protected; LDH release (%) was 35+/-3 in vehicle-treated hypoxic PT and 21+/-2 in IDN-8050-treated hypoxic PT (P<0.01, n=6). To investigate the mechanism of protection and examine the role of caspase-1 specifically, PT were isolated in parallel from wild-type and caspase-1- deficient (-/-) mice. PT from caspase-1-/-mice demonstrated less hypoxia-induced membrane injury. LDH release was 37+/-2 in wild-type hypoxic PT and 28+/-2 in caspase-1-/-hypoxic PT (P<0.01, n=12). IL-18 was detected in PT by immunoblotting and ELISA. PT pre-incubated with IL-18 binding protein, an inhibitor of IL-18, were not protected. CONCLUSIONS: These studies demonstrate a deleterious effect of the proinflammatory caspase, caspase-1, on PT in vitro in the absence of inflammatory cells and vascular effects.     

Interleukin-18 Affects Local Cytokine Expression But Does Not Impact on the Development of Kidney Allograft Rejection

Interleukin-18 is predominantly a macrophage-derived cytokine with a key role in inflammation and cell-mediated immunity. Having previously demonstrated IL-18 upregulation in a rat model of kidney rejection, here we examined IL-18 in a fully MHC-mismatched murine model of acute kidney rejection using IL-18-deficient recipients (IL-18-/-) and animals administered neutralizing IL-18 binding protein (IL-18BP). Gene expression of IL-18 and its receptor were significantly upregulated in allografts compared to isografts, as was the cellular infiltrate (T cells and macrophages) (p < 0.001). Allografts developed kidney dysfunction (p < 0.05) and tubulitis (p < 0.01) not observed in controls. There was a significant reduction in gene expression of IL-18 downstream pro-inflammatory molecules (iNOS, TNFalpha and IFNgamma) in IL-18-/- recipients (p < 0.01), and IL-18BP-treated animals. The CD4+ infiltrate and IL-4 mRNA expression was greater in the IL-18-/- recipients than wild-type (WT) allografts and IL-18BP-treated animals (p < 0.05), suggesting a Th2-bias which was supported by IFNgamma and IL-4 ELISPOT data and an increased eosinophil accumulation (p < 0.001). Neither IL-18 deficiency nor neutralization prevented renal dysfunction or tubulitis. This study demonstrates increased production of IL-18 in murine kidney allograft rejection and provides evidence that IL-18-induced pathways of inflammation are active. However, neither IL-18 deficiency nor neutralization was protective against the development of allograft rejection.     

Involvement of endogenous interleukin-10 and tumor necrosis factor-alpha in renal ischemia-reperfusion injury

BACKGROUND: Ischemia followed by reperfusion is a common clinical event associated with a pro-inflammatory response leading to organ dysfunction. The aim of the present study is to evaluate the interplay between this pro-inflammatory response and apoptosis. We investigated the role of the pro-inflammatory mediator tumor necrosis factor-alpha (TNF-alpha) and the anti-inflammatory mediator interleukin-10 (IL-10) in inflammation and apoptosis after renal ischemia reperfusion. METHODS: Male Swiss mice were subjected to 45 min of ischemia followed by reperfusion and subsequently administered neutralizing Abs against either TNF-alpha (TN3), IL-10 (JES5-2A5) or control. RESULTS: After 1 day of reperfusion, anti-TNF-alpha treatment reduced whereas anti-IL-10 treatment exacerbated postischemic renal injury, inflammation, and, to a lesser extent, apoptosis as measured by changes in blood urea nitrogen content, immunohistologically detectable renal TNF-alpha protein and neutrophils, histological integrity of renal parenchyma, and DNA ladder formation. Furthermore, anti-IL-10 treatment enhanced major histocompatibility complex class I and II expression at day 7 as measured by enzyme immunoassay and immunohistology. CONCLUSIONS: These data indicate that the extent of reperfusion-induced apoptosis is modulated by the inflammatory response, during which locally produced TNF-alpha plays a significant role in the development of tissue injury. Subsequently, this pro-inflammatory reaction is followed by endogenous production of the anti-inflammatory cytokine IL-10, which serves as a physiological counterbalance to the effects of TNF-alpha. These novel pathophysiological insights may provide new basis for the development of tools for limiting ischemia and reperfusion injury.     

IL-18 contributes to renal damage after ischemia-reperfusion

IL-18 is a proinflammatory cytokine produced by macrophages and other cell types present in the kidney during ischemia-reperfusion injury (IRI), but its role in this injury is unknown. Here, compared with wild-type mice, IL-18(-/-) mice subjected to kidney IRI demonstrated better kidney function, less tubular damage, reduced accumulation of neutrophils and macrophages, and decreased expression of proinflammatory molecules that are downstream of IL-18. For determination of the relative contributions of leukocytes and parenchymal cells to IL-18 production and subsequent kidney damage during IRI, bone marrow-chimeric mice were generated. Wild-type mice engrafted with IL-18(-/-) hemopoietic cells showed less kidney dysfunction and tubular damage than IL-18(-/-) mice engrafted with wild-type bone marrow. In vitro, macrophages produced IL-18 mRNA and protein in response to ischemia. These data suggest bone marrow-derived cells are the key contributors to IL-18-mediated effects of renal IRI. Finally, similar to IL-18(-/-) mice, pretreatment of wild-type mice with IL-18-binding protein was renoprotective in this model of IRI. In conclusion, IL-18, derived primarily from cells of bone marrow origin, contributes to the renal damage observed during IRI. IL-18-binding protein may have potential as a renoprotective therapy.     

IL-18 translational inhibition restricts IFN-gamma expression in crescentic glomerulonephritis

BACKGROUND: Interleukin-18 (IL-18), a potent inducer of interferon gamma (IFN-gamma) production, is a cytokine involved in the cell-mediated immune response that is expressed during inflammatory and pathologic conditions. IFN-gamma plays a role in the development of some models of glomerulonephritis (GN); however, the role of IL-18 in the production of IFN-gamma during these pathologies has not been studied. METHODS: Rat IL-18 cDNA was isolated and the regulation of IL-18 gene expression was studied. IFN-gamma and IL-18 expression were determined in anti-glomerular basement membrane (GBM) antibody (Ab)-induced GN. Recombinant active IL-18 (rIL-18) was used to further identify its effect on IFN-gamma production during this GN. Glomerular injury and levels of IFN-gamma were assayed in Wistar Kyoto (WKY) rats with anti-GBM GN in the presence or absence of rIL-18. RESULTS: Rat IL-18, similar to the mouse clone, requires processing by the IL-1beta converting enzyme to become activated. A rat IL-18 5'-untranslated region (UTR) translational inhibitor was identified that strongly inhibited the synthesis of IL-18. This translational inhibitor with different lengths (180 and 130 bp) was highly expressed during GN and correlated with minimal IFN-gamma mRNA expression. Injection of recombinant active IL-18 in WKY rats with anti-GBM GN was associated with an increase of glomerular IFN-gamma levels, proliferating cell nuclear antigen (PCNA)-ED1+ cells, and PCNA-CD8+ cells, with worsening of glomerular injury. CONCLUSION: These data suggest that the translational control of IL-18 expression by its 5'-UTR limits the production of IL-18, resulting in restricted expression of mRNA and protein IFN-gamma in this model of GN. Furthermore, it was suggested that possible IL-18/IFN-gamma induction of local proliferation of macrophages and CD8+ cells might be an important mechanism for amplifying CD8+-mediated macrophage-dependent GN.     

Macrophage-derived interleukin-18 in experimental renal allograft rejection.

BACKGROUND: Interleukin 18 (IL-18) is primarily a macrophage-derived, pro-inflammatory cytokine. As macrophages can act as effector cells in acute rejection, we examined the role of IL-18 in a rat model of acute renal allograft rejection. METHODS: Life-sustaining orthotopic DA to Lewis allograft and Lewis-Lewis isograft kidney transplants were performed. In the same model, macrophage-depleted animals, achieved with liposomal-clodronate therapy, were also studied. Macrophage (ED1+) accumulation and IL-18 expression was assessed by immunohistochemistry. CD11b+ cells (macrophages) were isolated from kidney and spleen by micro beads. Real-time PCR was used to assess IL-18 and INF-gamma mRNA expression in tissue and cell isolates. RESULTS: Allografts, but not isografts, developed severe tubulo-interstitial damage and increased serum creatinine by day 5 (P<0.001). Immunohistochemistry revealed a greater ED1+ cell accumulation in day 5 allografts compared with isografts (P<0.001). IL-18 mRNA expression was increased 3-fold in allografts compared to isografts (P<0.001). Accordingly, IL-18 protein was increased in allografts (P<0.001), and was predominantly expressed by ED1+ macrophages. CD11b+ macrophages isolated from allografts had a 6-fold upregulation of IL-18 mRNA expression compared to isograft macrophages (P<0.001). Macrophage depletion resulted in a marked attenuation of allograft rejection, ED1+ and IL-18+ cells were significantly reduced (P<0.05) as was IL-18 mRNA expression (29.28+/-2.85 vs 62.48+/-3.05, P<0.001). INF-gamma mRNA expression (P<0.01) and iNOS (P<0.001) production were also significantly reduced in the macrophage-depleted animals. CONCLUSION: This study demonstrates that IL-18 is significantly increased during acute rejection and is principally produced by intra-graft macrophages. We hypothesize that IL-18 upregulation may be an important macrophage effector mechanism during the acute rejection process.     

Novel pro-inflammatory interleukins: potential therapeutic targets in rheumatoid arthritis.

Among potential targets for nonspecific anti-inflammatory immunointervention, three pro-inflammatory interleukins (ILs) have recently been found to play a pivotal role in rheumatoid arthritis (RA). IL-15 has both chemoattractant and proinflammatory properties and may promote bone destruction. IL-17, a product of T lymphocytes, has proinflammatory effects and induces production of metalloproteinases such as MMP-1. IL-18 not only has proinflammatory, angiogenic, and chemoattractant effects but also promotes cartilage destruction. These cytokines are potential targets for specific or nonspecific anti-inflammatory therapy. Thus, blocking IL-15 by its receptor reduces the severity of experimental collagen-induced arthritis (CIA). In this model, IL-17 levels fall after administration of anti-inflammatory cytokines such as IL-4 or IL-13. Finally, monoclonal anti-IL-18 antibodies prevent streptococcal cell wall arthritis, and IL-18 binding protein, which is a naturally occurring IL-18 inhibitor, prevents CIA.     

Involvement of interleukin-18 in patients on maintenance haemodialysis

Maintenance dialysis induces a clinical state of immunodeficiency. The pathway of circulating T cells from haemodialyzed patients is changed and characterized by an increase of Th1 cells. The unbalanced T helper differentiation derives from an altered regulation of interleukin-12 (IL-12), which represents an important inducer of Th1. IL-18 is a pro-inflammatory cytokine expressed by a variety of cell types that is structurally related to the Th1 family and shares biological properties with IL-12 as the promotion of Th1 responses. To explain the involvement of IL-18 in the typical disorders of dialysis, we analyzed IL-18 serum levels in a group of haemodialyzed patients. We enrolled 16 patients on chronic haemodialysis (HD) treatment for end-stage renal failure and 16 healthy volunteers as the control group. IL-18 levels were assessed by immunoenzymatic methods (detection limit was <12.5 pg/ml). HD patients strongly showed higher IL-18 serum levels compared to healthy donors (508.47 +/- 314.39 vs. 193.44 +/- 56.33 pg/ml, p < 0.005). Moreover, IL-18 levels in HD directly correlated to dialytic age (Rho = 0.544, p = 0.0419) and indirectly to Kt/V (Rho = 0.703, p = 0.0086). Our data represent the first evidence of the relation between IL-18 serum levels and HD. In the light of our results, we think that the unbalanced T helper differentiation may depend, at least in part, on an abnormality in the IL-18 production.     

Adipose-derived stem cell and their extracellular vesicles ameliorates immune function,and cardiac markers in experimental model of cardiorenal syndrome type III: TNF-α, IFN-γ and IL-10 cytokine production and their correlation with genotype

Cardio-renal syndrome (CRS) denotes the convergence of heart-kidney interactions across several mechanisms. The current study is conducted to evaluate the anti-inflammatory role of adipose tissue-derived stem cells (ASCs) versus adipose stem cell-derived extracellular vesicles (ADSCs-EVs) in experimental model of cardiorenal syndrome type III. The study was conducted on 50 male rats that were equally divided to: group I (control group); Group II (experimental cardiorenal syndrome group) which induced by right renal artery ligation (ICRSIII); Group III (Sham-operated control group) which underwent surgical incision without renal artery ligation; Group IV (ICRSIII which received ADSCs-extracellular vesicles (ADSCs-EVs); Group V (ICRSIII which received adipose tissue stem cells (ASCs). Assessment of pro-inflammatory cytokines; IL-10, IL-1α, IL-6, IL-1 β, IFN-γ, NF-α and their mRNA gene expression quantitation, (NGAL), and brain natriuretic peptide (BNP) as markers of cardiac dysfunction, as well as histopathological examination of renal tissue was examined by H& E, Masson trichrome and periodic acid-Schiff stains (PAS). The ICRS group exhibited significant acute tubular injury with tubular dilation, loss of brush borders, epithelial flattening, and occasional sloughed cells in lumen. Use of either ADSCs-EVs or ASCs significantly ameliorated the histological findings of tubular injury. Proinflammatory cytokines, BNP and NGAL were significantly elevated in ICRSIII group as compared to all other studied groups. Administration of ADSCs-EVs or ASCs led to significant decrease in all proinflammatory cytokines as well as BNP and NGAL levels with no significant difference between them. In conclusion, ADSCs-EXs and ASCs exhibited significant repairing effects in experimental-induced cardiorenal syndrome type III as evidenced by amelioration of histological findings of tubular injury, anti-inflammatory effects, and the significant decrease in markers of cardiac dysfunction. ADSC-EVs reprogramed injured cardiac cells by activating regenerative processes.     

Comparative analysis of two low-level laser doses on the expression of inflammatory mediators and on neutrophils and macrophages in acute joint inflammation

Synovial membrane inflammation plays an important role in osteoarthritis (OA) pathophysiology. The synovial tissue of patients with initial OA is characterized by mononuclear cell infiltration and the production of pro-inflammatory cytokines and other mediators of joint injury. The study aims to evaluate the effect of low-level laser therapy (LLLT) at doses of 2 and 4 J on joint inflammation in rats induced by papain through histopathological analysis, differential counts of inflammatory cells; gene expression of IL-1β, IL-6, and IL-10; and TNF-α protein expression. Male Wistar rats (20) were randomly divided (5 animals each) into a negative control group, an inflammation injury positive control group, a 2-J LLLT group subjected to injury and treated with 2 J of LLLT, and a 4-J LLLT group subjected to injury and treated with 4 J of LLLT. The animals were subjected to joint inflammation (4 % papain solution) and treated with LLLT. On the day of euthanasia, articular lavage was collected and centrifuged. The supernatant was analyzed for TNF-α protein expression by ELISA and IL-1β, IL-6, and IL-10 mRNA by RT-PCR. The joint tissue was also examined histologically. ANOVA with Tukey's post hoc test was used for comparisons. All data were expressed as means ± S.D. (p?<?0.05). Both laser modalities were efficient in reducing cellular inflammation and decreasing the expression of IL-1β and IL-6. However, the 2-J treatment led to more reduction in TNF-α than the 4-J treatment. A single application of LLLT with 2 J was more efficient in modulating inflammatory mediators and inflammatory cells.     

Dentritic cell derived IL-18 production is inhibited by rapamycin and sanglifehrin A, but not cyclosporine A

Interleukin-18 (IL-18), a product of dendritic cells (DC), is a pro-inflammatory cytokine involved in the pathogenesis of allograft rejection, vascular disease, arthritis and diabetes. Rapamycin (Rapa) is an immunosuppressant that inhibits T cell mTOR kinase activation. In contrast, Sanglifehrin A (SFA), is a cyclophilin-binding immunosuppressant that does not act on calcineurin phosphatases but appears to inhibit IL-2-dependent T cell proliferation. Rapa and SFA exert some immunosuppressive effects on DC by inhibiting IL-12 production, although their effects on DC have not been investigated as comprehensively as those on T cells. We aimed to determine the impact of these drugs on DC IL-18 synthesis in vivo and in vitro. We found in vivo that LPS-stimulated OX62(+) DC produced significantly more IL-18 mRNA, compared to OX62(+) DC depleted splenocytes (p<0.01) and non-LPS-stimulated OX62(+) DC (p<0.01). OX62(+)CD4(+) and OX62(+)CD4(-) cells produced similar amounts of IL-18 mRNA. Rapa and SFA, but not CsA, significantly inhibited IL-18 production from OX62(+) DC in vitro, in a dose-dependent manner (p<0.05). In vivo IL-18 production was also inhibited by Rapa and SFA in splenic OX62(+) DC (p<0.01). Finally, inhibition of IL-18 production by Rapa and SFA was independent of the FK506 or cyclophilin pathways, respectively. In conclusion, Rapa and SFA, but not CsA, block IL-18 production and this novel Rapa blockade effect on IL-18 may contribute to the ability of Rapa to inhibit chronic allograft nephropathy and restenosis.     

Influence of albumin on expression of NLRP3 inflammasome in renal tubular epithelial cells

Objective To investigate the effect of albumin on expression of NLRP3 inflammasome and its downstream cytokines IL-1β and IL-18 in tubular epithelial cells. Methods Thirty mesangioproliferative glomerulonephritis (MsPGN) patients with different levels of proteinuria were selected, and their renal biopsy samples were stained by PAS and Masson to observe tubular epithelial cells injury and inflammatory cells infiltration. NLRP3, caspase-1, IL-1β and IL-18, as well as different inflammatory cells, were detected by immunohistostaining. In vitro, Western blotting and real-time PCR were employed to detect NLRP3, caspase-1, IL-1β and IL-18 protein and mRNA in HK-2 cells stimulated by bovine serum albumin (BSA) (20 g/L). Results In MsPGN patients with high levels of proteinuria, there were obvious renal tubular epithelial cell injury and inflammatory cells infiltration (all P＜0.05), and the expressions of NLRP3, caspase-1, IL-1β and IL-18 were up-regulated compared to patients with low levels of proteinuria (all P＜0.05). Furthermore, IL-1β and IL-18 expressions were positively correlated with the degree of proteinuria (r=0.836, P＜0.05; r=0.901, P＜0.05). NLRP3, caspase-1, IL-1β and IL-18 protein and mRNA were significantly increased in HK-2 cells stimulated by BSA compared to the control group (all P＜0.05). Conclusions Albumin is able to induce NLRP3 inflammasome activation in tubular epithelial cells, which may be the mechanism of tubulointerstitial injury and inflammation caused by proteinuria.     

Interleukin-17 stimulates release of interleukin-8 by human airway smooth muscle cells in vitro: a potential role for interleukin-17 and airway smooth muscle cells in bronchiolitis obliterans syndrome.

Bronchiolitis obliterans syndrome is the major constraint on the long-term survival after lung transplantation. Both neutrophils and interleukin (IL)-8, a potent neutrophil attractant, have been shown to play an important role in the pathophysiology of obliterative bronchiolitis. We investigated the potential role of human airway smooth muscle cells in obliterative bronchiolitis by studying their release of IL-8 after stimulation with IL-17, a novel T-cell-derived chemokine capable of attracting and activating neutrophils. We demonstrated a significant increase in IL-8 release, reaching a concentration of 86.6 ng/ml (SEM 1.9 ng/ml) with 100 ng/ml IL-17 (p < 0.01, n = 4), as compared with non-stimulated cells. This IL-17-mediated IL-8 release could not be inhibited by dexamethasone. We conclude that human airway smooth muscle cells may play an important pro-inflammatory role in neutrophilic inflammatory diseases such as chronic rejection after lung transplantation; furthermore, IL-17 may be the link between lymphocytes and neutrophils.     

IL-1 8在内毒素诱导大鼠肝损伤中的变化及中药腑安的作用

目的：研究白细胞介素－18（IL－18）在内毒素诱导大鼠肝损伤中的变化及中药腑安颗粒防治肝损伤的作用机理。方法：通过向大鼠腹腔内注射O111B4标准大肠杆菌加硫酸钡混悬液,建立实验性腹膜炎内毒素血症的动物模型,诱发大鼠肝损伤。检测血中内毒素（ET）、IL－18、谷丙转氨酶（ALT）的水平及肝组织病理学变化,并与腑安治疗组相比较。结果：实验性腹膜炎内毒素血症诱发的肝损伤中,大鼠血浆中内毒素及血清中的ALT含量升高,腑安治疗组中,内毒素及ALT水平均低于肝损伤模型组（P＜0．01）。模型组大鼠血清中IL－18显著升高,与ALT水平呈正相关。经腑安颗粒治疗后,可降低血清中IL－18。结论：内毒素诱导肝损伤的程度与血清中IL－18的升高呈正相关,表明IL－18是内毒素诱导肝损伤中的重要诱导因子,中药腑安颗粒保护肝脏的作用机制之一可能是通过降低IL－18水平而实现。     

Elevation of serum interleukin-18 levels and activation of Kupffer cells in biliary atresia

BACKGROUND/PURPOSE: Interleukin-18 (IL-18)/interferon-gamma-inducing factor (IGIF) is a novel proinflammatory cytokine that can induce interferon gamma (IFN-gamma). In addition, IL-18 enhances intracellular adhesion molecule-1 (ICAM-1) expression as well as Fas ligand (FasL) expression, and induces apoptosis in hepatic injury. The aim of this study was to clarify the potential role of IL-18 in the pathogenesis of the progressive inflammation and fibrosis in biliary atresia (BA). METHODS: Six children with BA before hepatic portoenterostomy (HPE), 13 with BA including 7 without jaundice and 6 with persistent jaundice after HPE, and 16 healthy controls were examined. Blood samples were obtained preoperatively from 6 patients, after HPE from 13, and after liver transplantation from 4. The IL-18 level was determined by an enzyme-linked immunosorbent assay (ELISA). Immunohistochemically, liver specimens from BA patients were studied using a monoclonal antibody to macrophage-associated antigen (CD68). RESULTS: IL-18 levels were elevated in the patients before HPE compared with those of the controls (349+/-54 pg/mL v. 138+/-13 pg/mL, P<.0001). After HPE, extremely high concentrations of IL-18 were observed in patients with persistent jaundice (532+/-95 pg/mL, P<.0001), and the IL-18 levels were significantly high even in the patients without jaundice (249+/-29 pg/mL, P<0.005). The high IL-18 level lasted for a long time even in the patients without jaundice after HPE. In contrast, the IL-18 levels immediately decreased after liver transplantation. Immunohistochemically, the number of CD68-positive Kupffer cells was significantly higher, and the size was larger in the livers of the patients than in the controls. The proliferation of CD68-positive cells was much more conspicuous in the liver specimens obtained during liver transplantation than in those at the time of HPE. CONCLUSIONS: Our findings showed elevation of serum IL-18 levels and activation of Kupffer cells in BA. IL-18 released from activated Kupffer cells might play an important role in the pathophysiology of the progressive inflammation and fibrosis in BA. Furthermore, IL-18 level may be related to the prognosis in patients with BA.     

Gene-gene,gene-environment,gene-nutrient interactions and single nucleotide polymorphisms of inflammatory cytokines

Inflammation plays a significant role in the etiology of type 2 diabetes mellitus(T2DM).The rise in the pro-inflammatory cytokines is the essential step in glucotoxicity and lipotoxicity induced mitochondrial injury,oxidative stress and beta cell apoptosis in T2 DM.Among the recognized markers are interleukin(IL)-6,IL-1,IL-10,IL-18,tissue necrosis factor-alpha(TNF-α),C-reactive protein,resistin,adiponectin,tissue plasminogen activator,fibrinogen and heptoglobins.Diabetes mellitus has firm genetic and very strong environmental influence; exhibiting a polygenic mode of inheritance.Many single nucleotide polymorphisms(SNPs) in various genes including those of pro and antiinflammatory cytokines have been reported as a risk for T2 DM.Not all the SNPs have been confirmed by unifying results in different studies and wide variations have been reported in various ethnic groups.The inter-ethnic variations can be explained by the fact that gene expression may be regulated by gene-gene,gene-environment and gene-nutrient interactions.This review highlights the impact of these interactions on determining the role of single nucleotide polymorphism of IL-6,TNF-α,resistin and adiponectin in pathogenesis of T2 DM.