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

6 Citations (Scopus)

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
StatePublished - May 1 2016

Fingerprint

Natural Killer T-Cells
Interleukins
Sepsis
Cytokines
Interleukin-10
Lipopolysaccharides
Inflammation
Punctures
Ligation
Mortality
Liver
Therapeutic Uses
Septic Shock
Genetic Therapy
Interferon-gamma
Tumor Necrosis Factor-alpha
Lymphocytes
Apoptosis

Keywords

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

ASJC Scopus subject areas

  • Hepatology

Cite this

Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells. / Yan, Jun; Mitra, Abhisek; Hu, Jiemiao; Cutrera, Jeffery J.; Xia, Xueqing; Doetschman, Thomas C; Gagea, Mihai; Mishra, Lopa; Li, Shulin.

In: Journal of Hepatology, Vol. 64, No. 5, 01.05.2016, p. 1128-1136.

Research output: Contribution to journalArticle

Yan, Jun ; Mitra, Abhisek ; Hu, Jiemiao ; Cutrera, Jeffery J. ; Xia, Xueqing ; Doetschman, Thomas C ; Gagea, Mihai ; Mishra, Lopa ; Li, Shulin. / Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells. In: Journal of Hepatology. 2016 ; Vol. 64, No. 5. pp. 1128-1136.
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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.",
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author = "Jun Yan and Abhisek Mitra and Jiemiao Hu and Cutrera, {Jeffery J.} and Xueqing Xia and Doetschman, {Thomas C} and Mihai Gagea and Lopa Mishra and Shulin Li",
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T1 - Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells

AU - Yan, Jun

AU - Mitra, Abhisek

AU - Hu, Jiemiao

AU - Cutrera, Jeffery J.

AU - Xia, Xueqing

AU - Doetschman, Thomas C

AU - Gagea, Mihai

AU - Mishra, Lopa

AU - Li, Shulin

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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.

AB - 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.

KW - Gp130.

KW - IL-10

KW - IL-6R

KW - Liver injury

KW - Natural killer T cells

KW - NF-rB

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