Interleukin‐38 protects against sepsis by augmenting immunosuppressive activity of CD4(+)CD25(+) regulatory T cells

Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) are required to limit immune‐induced pathology and to maintain homeostasis during the early‐phase of sepsis. This study aimed to investigate the role of interleukin (IL)‐38, a newly described member of the IL‐1 cytokine family, in mediated immune response of CD4(+)CD25(+) Tregs in sepsis. Here, we provide evidence that expressions of IL‐38 and its receptor were detected in murine CD4(+)CD25(+) Tregs. Stimulation of CD4(+)CD25(+) Tregs with LPS markedly up‐regulated the expression of IL‐38. Treatment with rmIL‐38 dramatically enhanced the immunosuppressive activity of CD4(+)CD25(+) Tregs after LPS stimulation and in septic mice induced by CLP, resulting in amplification of helper T cell (Th) 2 response and reduction in the proliferation of effector T cells. These effects were robustly abrogated when anti–IL‐38 antibody was administered. Administration of rmIL‐38 improved the survival rate of CLP mice. In addition, CD4(+)CD25(+) Tregs depletion before the onset of sepsis obviously abolished IL‐38–mediated protective response. These findings suggest that IL‐38 enhances the immunosuppressive activity of CD4(+)CD25(+) Tregs, which might contribute to the improvement of host immune function and prognosis in the setting of sepsis.