Background/Purpose: IL-38 (IL-1F10) was originally described as an IL-1 family cytokine, and named IL-1HY2. The IL-38 gene is located in the IL-1 family cluster on chromosome 2, next to the genes encoding the IL-1 receptor antagonist (IL-1Ra) and the IL-36 receptor antagonist (IL-36Ra). IL-38 shares 37% homology with IL-1Ra, 43% homology with IL-36Ra, and has a three-dimensional structure similar to IL-1Ra. IL-38 was recently shown to inhibit Candida albicans-induced IL-17 and IL-22 production by human memory T cells. However, the role of IL-38 in inflammatory diseases such as RA remains unclear.

Methods: We established several clones of mouse anti-human IL-38 mAb. One anti-human IL-38 mAb (H127C, mouse IgG2a) can be used for sandwich ELISAs and immunohistochemistry. To determine the expression pattern of the IL-38 gene, a panel of cDNA derived from normal lung, pancreas, spleen, muscle, synoviocyte samples and peripheral blood mononuclear cells (PBMCs) was analyzed by quantitative real time-PCR (qRT-PCR), using primers specific to human IL-38. The serum levels of IL-38 in 137 RA and 26 OA patients, and in 56 healthy donors, were determined by ELISA. Synovial tissue samples were also obtained from 7 RA and 3 OA patients. We used immunohistochemistry to identify IL-38, prolyl-4-hydroxylase-positive fibroblasts, and CD68-positive macrophages. Arthritis was initiated in mice lacking IL-38, as well as their wild-type littermates, via intraperitoneal administration of K/BxN mouse serum. Total RNA was isolated from mouse ankle joints and IL-1ß and IL-6 mRNA were quantified by qRT-PCR.

Results: The IL-38 transcripts were strongly expressed in the lung, spleen, and synoviocytes, and at a lower level in the pancreas and muscle. Further, strong mRNA expression of the IL-38 gene was also observed in PBMCs obtained from 2 healthy donors. The serum levels of IL-38 were 5.7 ± 0.4 pg/mL, 2.8 ± 0.8 pg/mL, and 2.8 ± 0.7 pg/mL in RA patients, OA patients, and healthy donors, respectively. Twenty-one of the 137 RA (15.3%) patients, 1 of the 26 OA patients (3.9%), and 5 of the 56 controls (8.9%) had IL-38 levels that were above the limit of detection of our ELISA system (10 pg/mL). Further, IL-38 protein was strongly expressed in the synovial lining of RA synovium. Serial sections indicated that synovial fibroblasts highly expressed IL-38 protein; CD68-positive macrophages barely expressed IL-38 in the RA synovium. In contrast, IL-38 protein was barely expressed in the synovial lining of OA synovium. Moreover, we found that IL-38-deficient mice exhibited significant exacerbation of their arthritis clinical scores, compared with their wild-type littermates. Correspondingly, histological measures of arthritis were also exacerbated, and accompanied by increased IL-1ß and IL-6gene expression in the ankles.

Conclusion: Our present study is the first to identify the presence of soluble IL-38 protein in the serum and its expression in the synovium of RA patients. IL-38 may play a role as an inhibitor in the pathogenesis of RA. 

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-38-a-new-factor-in-rheumatoid-arthritis/