Interleukin (IL)-18, a member of the IL-1 superfamily, is a pro-inflammatory cytokine that is structurally similar to IL-1β. IL-18 promotes the production of interferon gamma (IFN-γ) and strongly induces a Th1 response. IL-18 drives the same myeloid differentiation factor 88 (MyD88)/nuclear factor kappa B (NF-κB) signaling pathway as IL-1β. In physiological conditions, IL-18 is regulated by the endogenous inhibitor IL-18 binding protein (IL-18BP), and the activity of IL-18 is balanced. It is reported that in several inflammatory diseases, the IL-18 activity is unbalanced, and IL-18 neutralization by IL-18BP is insufficient. IL-18 acts synergistically with IL-12 to induce the production of IFN-γ as a Th1 cytokine, and IL-18 acts alone to induce the production of Th2 cytokines such as IL-4 and IL-13. In addition, IL-18 alone enhances natural killer (NK) cell activity and FAS ligand expression. The biological and pathological roles of IL-18 have been studied in many diseases. Here we review the knowledge regarding IL-18 signaling and the role of IL-18 in inflammatory kidney diseases. Findings on renal injury in coronavirus disease 2019 (COVID-19) and its association with IL-18 will also be presented.

Background: Interleukin (IL)-18 is markedly elevated in systemic inflammatory diseases that cause the ‘cytokine storm’ such as adult-onset Still’s disease (AOSD) and hemophagocytic lymphohistiocytosis (HLH). The differences in IL-18 between AOSD and HLH, especially in adults, is uncertain. Macrophage activation syndrome (MAS), a form of secondary HLH, is often difficult to differentiate cases of AOSD that include MAS from other secondary HLH. In this case-control study, we investigated whether serum IL-18 levels could be a useful biomarker for the differential diagnosis of AOSD with or without MAS (AOSD group) and other secondary HLH in adults (adult HLH group).Patients and Methods: We enrolled 46 patients diagnosed with AOSD including 9 patients with MAS and 31 patients in the adult HLH group, which excluded AOSD-associated MAS. The clinical features and laboratory data were compared between the AOSD and adult HLH groups. In addition, we subdivided the AOSD group (with or without MAS) and the adult HLH group (whether lymphoma-associated or not) and compared the four groups. A logistic regression analysis was used to identify factors with high efficacy in differentiating the two groups, followed by a receiver operating characteristic (ROC) curve analysis to evaluate the differential diagnostic ability of IL-18. We analyzed the correlation between IL-18 and various laboratory parameters in the AOSD group.Results: Serum IL-18 levels of patients in the AOSD groups were significantly higher than those of the adult HLH groups, and were closely correlated with ferritin, soluble interleukin-2 receptor (sIL-2R), and other laboratory data. Univariate and multivariate logistic regression analyses revealed that IL-18, sIL-2R, and ‘arthralgia or arthritis’ are independent factors useful in the differential diagnosis of AOSD from adult HLH. In the differential diagnosis of both groups, the area under the curve obtained from the ROC curve of IL-18 with a cutoff value of 18,550 pg/mL was 0.91 (95% confidence interval 0.83–1.00; sensitivity 90.3%, specificity 93.5%), and the differential diagnosis ability of IL-18 was superior to that of other laboratory data.Conclusions: IL-18 could be a useful biomarker for the differential diagnosis of AOSD and adult HLH.

Biomarkers of disease activity in lupus nephritis (LN) are needed. Ideally, such biomarkers would be capable of detecting early sub-clinical disease and could be used to gauge response to therapy, thus obviating the need for serial renal biopsies. Much of the focus in the search for LN biomarkers has been on the measurement of urinary chemokines and cytokines in LN patients. However, these have yet to be widely implemented in clinical practice. Kidney injury molecule-1 (Kim-1) is expressed in damaged tubules, but whether urinary (u) and tubular (t)-Kim-1 could serve as a biomarker of active LN is unknown. To investigate the disease activity and histological findings in LN, we evaluated u-Kim-1 levels and t-Kim-1 cells in patients with systemic lupus erythematosus (SLE). We measured u-Kim-1 levels and stained t-Kim-1 expression in 57 patients with LN using an ELISA and immunohistochemistry staining. Patients were classified into two groups (active LN, n = 37; inactive LN, n = 20) based on the presence of active renal disease according to the renal SLE disease activity index. correlations of clinical, laboratory data, and histological findings with urinary and t-Kim-1 expression were assessed. The u-Kim-1 levels were significantly correlated with the expression of t-Kim-1 (R = 0.64; P = 0.004) in the SLE patients. The active LN patients exhibited elevated u-Kim-1 levels compared to the inactive LN patients. The number of t-Kim-1 cells was also correlated with histological findings (both glomerular and interstitial inflammation). The u-Kim-1 levels were also correlated with proteinuria and tubular damage in the active LN group. The number of t-Kim-1 cells at baseline was significantly correlated with the estimated glomerular filtration rate (R = 0.72; P = 0.005) and serum creatinine (R = 0.53; P = 0.005) after 6–8 months of treatment. These data suggest the potential use of the u-Kim-1 levels to screen for active LN and for the estimation of t-Kim-1 expression in renal biopsies to predict renal damage, ongoing glomerular nephritis and tubulointerstitial inflammation, and tubular atrophy.

The proinflammatory cytokine interleukin (IL)-18 is an important mediator of the organ failure induced by endotoxemia. IL-18 (known as an interferon-gamma (IFN-γ) inducing factor), and other inflammatory cytokines have important roles in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). We investigated the effect of inflammatory cytokines and Toll-like receptor 4 (TLR4) expression, an event that is accompanied by an influx of monocytes, including CD4⁺ T cells and antigen-presenting cells (APCs) in IL-18Rα knockout (KO) mice and wild-type (WT) mice after LPS injection. In the acute advanced phase, the IL-18Rα KO mice showed a higher survival rate and a suppressed increase of blood urea nitrogen, increased levels of proinflammatory cytokines such as IFN-γ and IL-18, the infiltration of CD4⁺ T cells and the expression of kidney injury molecule-1 as an AKI marker. In that phase, the renal mRNA expression of the M1 macrophage phenotype and C-C chemokine receptor type 7 as the maturation marker of dendritic cells (DCs) was also significantly decreased in the IL-18Rα KO mice, although there were small numbers of F4/80⁺ cells and DCs in the kidney. Conversely, there were no significant differences in the expressions of mRNA and protein TLR4 after LPS injection between the WT and IL-18Rα KO groups. Our results demonstrated that the IL-18Rα-mediated signaling pathway plays critical roles in CD4⁺ T cells and APCs and responded more quickly to IFN-γ and IL-18 than TLR4 stimulation in the pathogenesis of LPS-induced AKI.

Interleukin (IL)-18 expression in synovial tissue correlates with the severity of joint inflammation and the levels of pro-inflammatory cytokines. However, the role of the IL-18/IL-18 receptor-alpha (Rα) signaling pathway in autoimmune arthritis is unknown. Wild-type (WT) and IL-18Rα knockout (KO) mice were immunized with bovine type II collagen before the onset of arthritis induced by lipopolysaccharide injection. Disease activity was evaluated by semiquantitative scoring and histologic assessment. Serum inflammatory cytokine and anticollagen antibody levels were quantified by an enzyme-linked immunosorbent assay. Joint cytokine and matrix metalloproteinases-3 levels were determined by a quantitative polymerase chain reaction. Splenic suppressors of cytokine signaling (SOCS) were determined by Western blot analysis as indices of systemic immunoresponse. IL-18Rα KO mice showed lower arthritis and histological scores in bone erosion and synovitis due to reductions in the infiltration of CD4+ T cells and F4/80+ cells and decreased serum IL-6, -18, TNF, and IFN-γ levels. The mRNA expression and protein levels of SOCS3 were significantly increased in the IL-18Rα KO mice. By an up-regulation of SOCS, pro-inflammatory cytokines were decreased through the IL-18/IL-18Rα signaling pathway. These results suggest that inhibitors of the IL-18/IL-18Rα signaling pathway could become new therapeutic agents for rheumatoid arthritis.