Cell Intrinsic IL-38 Affects B Cell Differentiation and Antibody Production

Abstract

IL-38 is an IL-1 family receptor antagonist with an emerging role in chronic inflammatory diseases. IL-38 expression has been mainly observed not only in epithelia, but also in cells of the immune system, including macrophages and B cells. Given the association of both IL-38 and B cells with chronic inflammation, we explored if IL-38 affects B cell biology. IL-38-deficient mice showed higher amounts of plasma cells (PC) in lymphoid organs but, conversely, lower levels of plasmatic antibody titers. Exploring underlying mechanisms in human B cells revealed that exogenously added IL-38 did not significantly affect early B cell activation or differentiation into plasma cells, even though IL-38 suppressed upregulation of CD38. Instead, IL-38 mRNA expression was transiently upregulated during the differentiation of human B cells to plasma cells in vitro, and knocking down IL-38 during early B cell differentiation increased plasma cell generation, while reducing antibody production, thus reproducing the murine phenotype. Although this endogenous role of IL-38 in B cell differentiation and antibody production did not align with an immunosuppressive function, autoantibody production induced in mice by repeated IL-18 injections was enhanced in an IL-38-deficient background. Taken together, our data suggest that cell-intrinsic IL-38 promotes antibody production at baseline but suppresses the production of autoantibodies in an inflammatory context, which may partially explain its protective role during chronic inflammation.

The emerging role of IL‐38 in diseases: A comprehensive review

“…IL-38 is reported to regulate the development of autoimmune diseases by inactivating immune cells and inflammatory responses through various mechanisms. 55,56 For example, IL-38 can inhibit the release of inflammatory cytokines and chemotaxis to inactivate inflammatory cells. Meanwhile, IL-38 promotes the activity of regulatory T cells (Treg) to suppress autoimmune responses.…”

Editorial for the Special Issue “Cytokines in Inflammatory Signaling”

“…In the realm of adaptive immunity, the role of IL-38 in B cell biology and its paradoxical effects on plasma cell generation and antibody production are revealed in another contribution to this Special Issue [ 7 ]. The nuanced understanding of IL-38’s function provided by this study is a testament to the complex nature of cytokine signaling and its impact on the immune response.…”

Role of IL-1 Family Cytokines IL-36, IL-37, IL-38 in Osteoarthritis and Rheumatoid Arthritis: A Comprehensive Review

“… 57 Regarding the role of IL-38 in B cells, IL-38 −/− mice have an increased number of plasma cells in lymphoid organs and low expression of IgA and IgM. 58 During B cell differentiation, IL-38 knockdown up-regulates levels of CD38, IL-6 in CD27 + B cells, and downregulates the expression of IgM, IgA and IgG. 58 Collectively, IL-38 may inhibit Th1, Th17, and B cells differentiation and up-regulate Treg and Th2 cells functions.…”