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.
Highlights
CD4+CD25+ regulatory T cells (Tregs) can regulate host responses to infections and tumours, and contribute to the prevention of allergies, autoimmune diseases and transplant rejection.[1,2,3,4] CD4+CD25+ Tregs are essential for maintenance of immune homeostasis and self-tolerance
It was reported that IL-38 levels were elevated in patients with sepsis, and administration of recombinant murine IL-38 in mice could protect against challenge with LPS and sepsis induced by caecal ligation and puncture (CLP) without affecting bacterial phagocytosis.[43]
The present study showed that early replenishment of IL-38 was associated with a higher survival rate in mice challenged with polymicrobial sepsis, indicating that IL-38–mediated responses in CD4+CD25+Tregs could restrain early hyper-inflammation and protect against septic complications
Summary
CD4+CD25+ regulatory T cells (Tregs) can regulate host responses to infections and tumours, and contribute to the prevention of allergies, autoimmune diseases and transplant rejection.[1,2,3,4] CD4+CD25+ Tregs are essential for maintenance of immune homeostasis and self-tolerance. IL-38 is extensively expressed in several tissues including spleen, thymus, foetal liver, placenta, lung and heart It is expressed in proliferating B cells and epithelia.[31] Interestingly, IL-38 can be released from apoptotic cells to control inflammatory macrophage and Th17 response.[32] IL-38 binds to the IL-36 receptor (IL-36R) and has been proposed as an IL-36R antagonist based on sequence homology studies.[33] The expression of IL-38 is correlated tightly with various inflammatory and autoimmune disorders such as infection, asthma, systemic lupus erythematosus, psoriatic arthritis and rheumatoid arthritis.[34,35,36,37,38,39,40,41,42,43] It was reported that IL-38 levels were elevated in patients with sepsis, and administration of recombinant murine IL-38 (rmIL-38) in mice could protect against challenge with LPS and sepsis induced by CLP without affecting bacterial phagocytosis.[43] little is known about the influence of IL-38 on the activity of CD4+CD25+ Tregs in sepsis-induced immune dysfunction. Our results identified a novel biological effect of IL-38 on host immune response and elucidated its potential mechanism in the pathogenesis of sepsis
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