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Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis.

ABSTRACT: 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 (R?) signaling pathway in autoimmune arthritis is unknown. Wild-type (WT) and IL-18R? 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-18R? 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-? levels. The mRNA expression and protein levels of SOCS3 were significantly increased in the IL-18R? KO mice. By an up-regulation of SOCS, pro-inflammatory cytokines were decreased through the IL-18/IL-18R? signaling pathway. These results suggest that inhibitors of the IL-18/IL-18R? signaling pathway could become new therapeutic agents for rheumatoid arthritis.

SUBMITTER: Nozaki Y

PROVIDER: S-EPMC7017073 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis.

Nozaki Yuji Y Ri Jinhai J Sakai Kenji K Niki Kaoru K Kinoshita Koji K Funauchi Masanori M Matsumura Itaru I

Cells 20191218 1

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 assessm ...[more]

PMID: 31861496

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Project description:INTRODUCTION: There has been no report in the literature of a soluble form of interleukin (IL)-18 receptor ? (IL-18R?). In this study, we evaluated the levels and characteristics of soluble IL-18R? (sIL-18R?) in the sera of patients with rheumatoid arthritis (RA) and compared these results to control populations. METHODS: The sIL-18R? complex was isolated from pooled human blood serum using an anti-IL-18R? monoclonal antibody affinity column. The purified sIL-18R? was then examined using Western blot analysis and used in experiments to evaluate the effects on an IL-18-responsive natural killer (NK) human cell line, NK0. An enzyme-linked immunosorbent assay was developed, and sera from 145 patients with RA, 6 patients with adult-onset Still's disease, 31 patients with osteoarthritis (OA), 39 patients with systemic lupus erythematosus (SLE) and 67 controls were tested, along with levels of immunoglobulin M, rheumatoid factor, anticyclic citrullinated peptide antibody, IL-18, IL-13 and interferon (IFN)-?. Area under the receiver operating characteristic curve (ROC-AUC) analysis was used to evaluate the diagnostic utility of the sIL-18R? complex. RESULTS: The isolated sIL-18R? complex can be associated with IL-18 and the soluble form of the IL-18R? chain. The sIL-18R? complex bound to the surface to the NK0 cell line, antagonized the stimulatory effects of IL-18 and IL-2 on the NK0 cell line and inhibited IFN-? production by the cells. The serum levels of sIL-18R? complex in RA (186.0 ± 33.5 ng/mL, n = 145) and adult-onset Still's disease (98.2 ± 8.9 ng/mL, n = 6) were significantly (P < 0.001) higher than those in the healthy controls (52.3 ± 8.5 ng/mL, n = 67), OA (38.6 ± 5.4 ng/mL, n = 31), SLE (44.6 ± 3.2 ng/mL, n = 39). The serum level of sIL-18R? complex was not significantly different between RA and adult-onset Still's disease patients. The serum levels of IL-18, IL-13 and IFN-? in the RA patients were significantly (P < 0.01) higher than in OA and SLE patients as well as healthy controls. ROC-AUC analysis of the serum concentration of sIL-18R? indicated that it was significantly diagnostic of RA. Moreover, a tumor necrosis factor inhibitor, etanercept, significantly (P < 0.0001) decreased levels of sIL-18R? in the sera of 29 RA patients 6 months after treatment. CONCLUSIONS: The sIL-18R? complex could be a potentially useful biomarker for the diagnosis of RA.

Dataset Information

Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis.

Publications

Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis.

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