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

Abstract

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.