IL-38: A new factor in rheumatoid arthritis

Abstract

The newly characterized cytokine IL-38 (IL-1F10) belongs to the IL-1 family of cytokines. Previous work has demonstrated that IL-38 inhibited Candida albicans-induced IL-17 production from peripheral blood mononuclear cells. However, it is still unclear whether IL-38 is an inflammatory or an anti-inflammatory cytokine. We generated anti-human IL-38 monoclonal antibodies in order to perform immunohistochemical staining and an enzyme-linked immunosorbent assay. While human recombinant IL-38 protein was not cleaved by recombinant caspase-1, chymase, or PR3 in vitro, overexpression of IL-38 cDNA produced a soluble form of IL-38 protein. Furthermore, immunohistochemical analysis showed that synovial tissues obtained from RA patients strongly expressed IL-38 protein. To investigate the biological role of IL-38, C57BL/6 IL-38 gene-deficient (−/−) mice were used in an autoantibody-induced rheumatoid arthritis (RA) mouse model. As compared with control mice, IL-38 (−/−) mice showed greater disease severity, accompanied by higher IL-1β and IL-6 gene expression in the joints. Therefore, IL-38 acts as an inhibitor of the pathogenesis of autoantibody-induced arthritis in mice and may have a role in the development or progression of RA in humans.

IL-38 overexpression induces anti-inflammatory effects in mice arthritis models and in human macrophages in vitro

“…Previously, it has been shown that IL-38 deficient mice exhibit more severe STIA than wild type mice 14. Our present study expands these results and demonstrates for the first time that AAV-mediated IL-38 overexpression exerted moderate but significant anti-inflammatory effects in mice with CIA or STIA.…”

“…Moreover, patients with systemic lupus erythematosus, chronic hepatitis B, myocardial infarction or childhood asthma have higher levels of serum IL-38 than control populations 7–13. IL-38 levels are also increased in the synovial membrane and sera from patients with RA compared with healthy controls 13 14. We have previously shown that IL-38 mRNA levels are enhanced in synovial membranes of patients with RA and in colons of patients with Crohn's disease.…”

“…Moreover, C57BL/6 mice deficient for IL-38 have a more severe K/BxN serum transfer-induced arthritis (STIA) together with a higher expression of IL-1β and IL-6 in the joints 14. Thus, IL-38 appears to be a potential negative regulator of inflammation during arthritis, but its exact biological effect in vitro and in vivo needs to be elucidated.…”

Cytokines in the pathogenesis of rheumatoid arthritis: new players and therapeutic targets

“…Further analysis is required to test this hypothesis. Takenaka et al investigated AIA in IL-38 KO and observed greater disease severity, accompanied by higher IL-1β and IL-6 gene expression in the joints compared to control mice [47]. Recently, Boutet et al demonstrated that adeno-associated virus-mediated IL-38 overexpression exerted moderate but significant anti-inflammatory effects in CIA and K/BxN serum transfer-induced arthritis (STIA) [48].…”

“…Of note, IL-38 overexpression did not induce the production of other anti-inflammatory cytokines, but reduced significantly IL-10 expression. IL-38 levels are increased in the synovial membrane and sera from patients with RA compared with healthy controls [47,49] IL-38 is expressed by keratinocytes, synovial fibroblast from patients with RA, as well as by human monocytes and type I macrophages polarized in vitro [41].…”