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 (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.
Highlights
Interleukin (IL)-18 is a proinflammatory cytokine produced by antigen-presenting cells (APCs) and T cells such as macrophages, dendritic cells (DCs) and CD4+ T cells
The results of our experiments demonstrated that the blockade of the IL-18Rα signaling pathway inhibited the proliferation of autoreactive T cells, and the suppression of Th1 cytokines and infiltrations of inflammatory cells such as CD4+ T cells and APCs
We investigated the effects of the expression of inflammatory cytokines in IL-18Rα KO
Summary
Interleukin (IL)-18 is a proinflammatory cytokine produced by antigen-presenting cells (APCs) and T cells such as macrophages, dendritic cells (DCs) and CD4+ T cells. Downstream from IL-18R, the signaling activates interleukin-1 receptor-associated kinase 4 (IRAK4) and the adaptor molecule MyD88, in a scenario similar to that of other IL-1 and Toll-like receptors (TLRs) [1,2,3]. Evidence has been presented that IL-18 plays a prominent role in the onset and maintenance of an inflammatory response during rheumatoid arthritis. It was reported that IL-18 expression in synovial tissue correlates with the severity of joint inflammation and the levels of pro-inflammatory cytokines tumor necrosis factor alpha (TNFα) and IL-1β [4]. Several studies have indicated that IL-18 may play an important role in the pathophysiology of collagen-induced arthritis (CIA), which is a well-established autoimmune animal model of human rheumatoid arthritis [5]. There are several reports that a local neutralization of IL-18 by the naturally
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