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.
Highlights
IL-38 (IL-1F10) was originally cloned as an IL-1 family cytokine, and named IL-1HY2 in 2001 [1]
Sandwich enzyme-linked immunosorbent assay (ELISA) analysis revealed that the level of IL-38 in the supernatants of human IL-38 cDNAtransfected 293T cells was 39.0 ng/mL
Our in vitro study showed that human IL-38 protein was not cleaved by recombinant caspase-1, chymase, or PR3 in vitro
Summary
IL-38 (IL-1F10) was originally cloned as an IL-1 family cytokine, and named IL-1HY2 in 2001 [1]. A human IL-38 cDNA sequence identified from a human fetal skin library encodes a 152-aminoacid precursor. Human IL-38 has 4 exons, and the IL-38 gene is located in the IL-1 family cluster on chromosome 2 next to the genes encoding IL-1 receptor antagonist (IL-1Ra) and IL-36 receptor antagonist (IL-36Ra). IL-38 shares 37% homology with IL1Ra, 43% homology with IL-36Ra and has a three-dimensional structure similar to IL-1Ra [2]. Immunohistochemical analysis using a polyclonal antibody against an IL-38-origin synthetic peptide (CTLPNRGLDRTKVP) has shown that the IL-38 protein is expressed in the basal epithelia of human skin and in proliferating. B cells of the tonsil [1].
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