title: Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
authors.forename: Abhisek
authors.initials: A
authors.lastname: Mitra
authors.affiliation: Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
authors.forename: Jiemiao
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
authors.forename: Jeffery J
authors.initials: JJ
authors.lastname: Cutrera
authors.affiliation: Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Xia
authors.affiliation: BIO5 Institute and Department of Cellular & Molecular Medicine, Tucson, AZ, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Doetschman
authors.affiliation: Department of Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
authors.forename: Mihai
authors.initials: M
authors.lastname: Gagea
authors.affiliation: Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
authors.forename: Lopa
authors.initials: L
authors.lastname: Mishra
authors.affiliation: Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. Electronic address: Sli4@mdanderson.org.
authors.forename: Shulin
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007378:Interleukins / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000276:immunology*; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; C486767:Il27 protein, mouse; D007378:Interleukins
keywords: Gp130; IL-10; IL-6R; Liver injury; NF-кB; Natural killer T cells; Sepsis