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Blockade of interleukin-6 signaling enhances hepatic steatosis but improves liver injury in methionine choline-deficient diet-fed mice.
Lab Invest. 2010 Aug; 90(8):1169-78.LI

Abstract

Inflammatory processes have an important role in the development of hepatic steatosis and progression to nonalcoholic steatohepatitis (NASH). Interleukin-6 (IL-6) is known to be a proinflammatory cytokine, but also promotes liver regeneration and protects the liver against various forms of damage. The role of IL-6/Glycoprotein 130 (GP130) in NASH remains unclear. In this study, we determined whether blocking IL-6/GP130 signaling prevents progression of steatohepatitis in a mouse NASH model. Six-week-old male C57/BL6 mice were fed either chow control or a methionine choline-deficient (MCD) diet for 8 weeks. Half of the MCD diet-fed mice were treated with 15 mg/kg rat anti-mouse IL-6 receptor antibody (MR16-1), intraperitoneally twice weekly, the remainder and chow-fed mice were injected with 15 mg/kg rat IgG as a control. Hepatic steatosis, injury, fibrosis, apoptosis, markers of lipid peroxidation/oxidant stress and IL-6-related gene expressions were evaluated. MR16-1 treatment decreased signal transducer and activator of transcription 3 activities and expression of suppressor of cytokine signaling 3 in MCD diet-treated mouse livers. Although this treatment enhanced intrahepatic lipid accumulation accompanied by increased sterol regulatory element-binding protein 1 and decreased peroxisome proliferator-activated receptor-alpha expression, elevated plasma alanine aminotransferase levels were improved with decreased plasma free fatty acid levels, lipid peroxidation/oxidant stress and hepatic apoptosis. Blocking IL-6/GP130 signaling by MR16-1 enhanced MCD diet-induced hepatic steatosis, but ameliorated liver injury. These findings suggest that hepatic IL-6 signaling has a protective role against the progression of hepatic steatosis but may enhance liver inflammation.

Authors+Show Affiliations

Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20368703

Citation

Yamaguchi, Kanji, et al. "Blockade of Interleukin-6 Signaling Enhances Hepatic Steatosis but Improves Liver Injury in Methionine Choline-deficient Diet-fed Mice." Laboratory Investigation; a Journal of Technical Methods and Pathology, vol. 90, no. 8, 2010, pp. 1169-78.
Yamaguchi K, Itoh Y, Yokomizo C, et al. Blockade of interleukin-6 signaling enhances hepatic steatosis but improves liver injury in methionine choline-deficient diet-fed mice. Lab Invest. 2010;90(8):1169-78.
Yamaguchi, K., Itoh, Y., Yokomizo, C., Nishimura, T., Niimi, T., Fujii, H., Okanoue, T., & Yoshikawa, T. (2010). Blockade of interleukin-6 signaling enhances hepatic steatosis but improves liver injury in methionine choline-deficient diet-fed mice. Laboratory Investigation; a Journal of Technical Methods and Pathology, 90(8), 1169-78. https://doi.org/10.1038/labinvest.2010.75
Yamaguchi K, et al. Blockade of Interleukin-6 Signaling Enhances Hepatic Steatosis but Improves Liver Injury in Methionine Choline-deficient Diet-fed Mice. Lab Invest. 2010;90(8):1169-78. PubMed PMID: 20368703.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Blockade of interleukin-6 signaling enhances hepatic steatosis but improves liver injury in methionine choline-deficient diet-fed mice. AU - Yamaguchi,Kanji, AU - Itoh,Yoshito, AU - Yokomizo,Chihiro, AU - Nishimura,Takeshi, AU - Niimi,Toshihisa, AU - Fujii,Hideki, AU - Okanoue,Takeshi, AU - Yoshikawa,Toshikazu, Y1 - 2010/04/05/ PY - 2010/4/7/entrez PY - 2010/4/7/pubmed PY - 2010/8/31/medline SP - 1169 EP - 78 JF - Laboratory investigation; a journal of technical methods and pathology JO - Lab. Invest. VL - 90 IS - 8 N2 - Inflammatory processes have an important role in the development of hepatic steatosis and progression to nonalcoholic steatohepatitis (NASH). Interleukin-6 (IL-6) is known to be a proinflammatory cytokine, but also promotes liver regeneration and protects the liver against various forms of damage. The role of IL-6/Glycoprotein 130 (GP130) in NASH remains unclear. In this study, we determined whether blocking IL-6/GP130 signaling prevents progression of steatohepatitis in a mouse NASH model. Six-week-old male C57/BL6 mice were fed either chow control or a methionine choline-deficient (MCD) diet for 8 weeks. Half of the MCD diet-fed mice were treated with 15 mg/kg rat anti-mouse IL-6 receptor antibody (MR16-1), intraperitoneally twice weekly, the remainder and chow-fed mice were injected with 15 mg/kg rat IgG as a control. Hepatic steatosis, injury, fibrosis, apoptosis, markers of lipid peroxidation/oxidant stress and IL-6-related gene expressions were evaluated. MR16-1 treatment decreased signal transducer and activator of transcription 3 activities and expression of suppressor of cytokine signaling 3 in MCD diet-treated mouse livers. Although this treatment enhanced intrahepatic lipid accumulation accompanied by increased sterol regulatory element-binding protein 1 and decreased peroxisome proliferator-activated receptor-alpha expression, elevated plasma alanine aminotransferase levels were improved with decreased plasma free fatty acid levels, lipid peroxidation/oxidant stress and hepatic apoptosis. Blocking IL-6/GP130 signaling by MR16-1 enhanced MCD diet-induced hepatic steatosis, but ameliorated liver injury. These findings suggest that hepatic IL-6 signaling has a protective role against the progression of hepatic steatosis but may enhance liver inflammation. SN - 1530-0307 UR - https://www.unboundmedicine.com/medline/citation/20368703/Blockade_of_interleukin_6_signaling_enhances_hepatic_steatosis_but_improves_liver_injury_in_methionine_choline_deficient_diet_fed_mice_ L2 - http://dx.doi.org/10.1038/labinvest.2010.75 DB - PRIME DP - Unbound Medicine ER -