Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells

Jun Yan, Abhisek Mitra, Jiemiao Hu, Jeffery J. Cutrera, Xueqing Xia, Thomas C Doetschman, Mihai Gagea, Lopa Mishra, Shulin Li

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Background & Aims Sepsis is an acute systemic inflammatory response to infection associated with high patient mortality (28-40%). We hypothesized that interleukin (IL)-30, a novel cytokine protecting mice against liver injury resulting from inflammation, would generate a protective effect against systemic inflammation and sepsis-induced death. Methods Sepsis was induced by lipopolysaccharide (LPS) or cecal ligation and puncture (CLP). The inhibitory effects of IL-30 on septic inflammation and associated therapeutic effects were determined in wild-type, IL30 (p28)-/-, IL10-/-, and CD1d-/- mice. Results Mice treated with pIL30 gene therapy or recombinant IL-30 protein (rIL30) were protected from LPS-induced septic shock or CLP-induced polymicrobial sepsis and showed markedly less liver damage and lymphocyte apoptosis than control septic mice. The resulting reduction in mortality was mediated through attenuation of the systemic pro-inflammatory response and augmentation of bacterial clearance. Mice lacking IL-30 were more sensitive to LPS-induced sepsis. Natural killer-like T cells (NKT) produced much higher levels of IL-10 and lower levels of interferon-gamma and tumor necrosis factor-alpha in IL-30-treated septic mice than in control septic mice. Likewise, deficiency in IL-10 or NKT cells abolished the protective role of IL-30 against sepsis. Furthermore, IL-30 induced IL-10 production in purified and LPS-stimulated NKT cells. Blocking IL-6R or gp130 inhibited IL-30 mediated IL-10 production. Conclusions IL-30 is important in modulating production of NKT cytokines and subsequent NKT cell-mediated immune regulation of other cells. Therefore, IL-30 has a role in prevention and treatment of sepsis via modulation of cytokine production by NKT.

Original languageEnglish (US)
Pages (from-to)1128-1136
Number of pages9
JournalJournal of Hepatology
Volume64
Issue number5
DOIs
Publication statusPublished - May 1 2016

    Fingerprint

Keywords

  • Gp130.
  • IL-10
  • IL-6R
  • Liver injury
  • Natural killer T cells
  • NF-rB

ASJC Scopus subject areas

  • Hepatology

Cite this