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

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• 作者：Jun Yan¹ ; Abhisek Mitra¹ ; Jiemiao Hu¹ ; Jeffery J. Cutrera¹ ; Xueqing Xia¹ ; Thomas Doetschman² ; Mihai Gagea³ ; Lopa Mishra⁴ ; Shulin Li¹ ; ^{Sli4@mdanderson.org" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ALT ; alanine aminotransferase ; CLP ; cecal ligation and puncture ; H&E ; hematoxylin and eosin ; IFN ; interferon ; IL ; interleukin ; KO ; knockout ; LPS ; lipopolysaccharide ; NKT cells ; natural killer like T cells ; PBS ; phosphate-buffered saline solution ; PCR ; polymerase chain reaction ; TNF ; tumor necrosis factor ; WT ; wild-type
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：64
• 期：5
• 页码：1128-1136
• 全文大小：2414 K

文摘

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.