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 (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.Cells 2020, 9, 11 2 of 18 occurring IL-18 binding protein (IL-18BP) or a systemic neutralization by specific antibodies results in the amelioration of CIA, associated with reduced inflammation and cartilage erosion [6][7][8].The inhibition of cytokine signaling by the suppressors of cytokine signaling (SOCS) family constitutes a major negative feedback mechanism to prevent runaway inflammation. The transcription of SOCS proteins is rapidly upregulated in cells stimulated with cytokines. The SOCS then reduce the impact of cytokines by interacting with Janus kinases (JAKs) and by other mechanisms [9]. The roles of SOCS1 and −3 are underscored by the higher levels of the proinflammatory p38α and p38β mitogen-activated protein kinases (MAPKs) observed in IL-18Rα-deficient mouse embryonic fibroblasts (MEFs) compared to wild-type (WT) and IL-18-deficient MEFs. Since both SOCS1 [10][11][12] and SOCS3 [13,14] interfere with the IL-1/TLR-MAPK/nuclear factor-kappa (NF-κ)B pathway signaling, the increase in activity of these kinases in IL-18Rα-deficient cells may be due to a lesser degree of inhibition resulting from the reduced levels of both of these SOCS family members.In the present study, we confirmed that IL-18Rα was aberrantly expressed in the lymph nodes (LN) and splenocytes of mice with lipopolysaccharide (LPS)-induced arthritis. We hypothesized that if arthritis becomes hyper-responsive to LPS, which is a component of Gram-negative bacteria, this hyper-responsiveness may increase the levels of circulating inflammatory cytokines such as TNF, interferon-gamma (IFN-γ), and IL-6 and result in the blocking ...

The role of IL-18 in addition to Th17 cytokines in rheumatoid arthritis development and treatment in women

“…In addition, many previous studies have been shown that serum and synovial IL‐18 levels are correlated with disease activity in RA and their pivotal role in maintaining the joint inflammation in RA, summarized in review papers 29 , 30 . The newest support for IL-18 therapeutic targeting in RA came from experiments with IL-18Rα knockout (KO) mice model of induced experimental arthritis 31 . The results from this study demonstrated that inhibition of the IL-18/IL-18Rα signaling pathway inhibited not only the proliferation of autoreactive T cells but also the suppression of IL-6, IL-18, TNF, and IFN-γ serum levels.…”

Cytokine Networks in the Pathogenesis of Rheumatoid Arthritis

“…Since IL-18 intracellular signal transduction is also mediated by several kinases, crosstalk cannot be suppressed and it is difficult to block signal transduction with JAK inhibitors. Recently, a study using a murine CIA model has suggested that inhibition of cytokine signaling by the SOCS family constitutes a major negative feedback mechanism to prevent runaway inflammation [180]. The transcription of SOCS proteins is rapidly upregulated in cells stimulated with cytokines.…”

The Immunomodulatory and Anti-Inflammatory Effect of Curcumin on Immune Cell Populations, Cytokines, and In Vivo Models of Rheumatoid Arthritis

“…Additionally, IL-18 induces the production of IL-17 [ 82 ], IL-32 [ 75 ], IL-2, IL-2Rα, TNF-α, GM-CSF, prostaglandin E2, MMP3, chemokines [ 78 ], adhesion molecules, and angiogenic factors [ 82 ]. In murine models of RA, mice with knockdown of IL-18Rα (IL-18 receptor α) presented decreased levels of IL-6, IL-18, TNF-α, IFN-γ, and MMP3, as well as less severe disease progression [ 83 ], which can implicate the importance of this cytokine in the course of this affliction. A research study published by Yin et al revealed that curcumin suppressed the secretion of IL-18 in mouse bone marrow-derived macrophages [ 84 ].…”