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. doi: 10.1038/labinvest.2010.75. Epub 2010 Apr 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / blood
  • Alanine Transaminase / metabolism
  • Animals
  • Choline / adverse effects
  • Choline / metabolism
  • Choline Deficiency / complications*
  • Choline Deficiency / metabolism
  • Diet / adverse effects*
  • Fatty Liver* / chemically induced
  • Fatty Liver* / metabolism
  • Fatty Liver* / prevention & control
  • Genes
  • Interleukin-6 / adverse effects
  • Interleukin-6 / metabolism
  • Lipid Peroxidation
  • Liver / metabolism
  • Male
  • Methionine / adverse effects
  • Methionine / deficiency
  • Methionine / metabolism
  • Mice
  • Mice, Inbred C57BL
  • PPAR alpha / adverse effects
  • PPAR alpha / metabolism
  • Receptors, Interleukin-6 / metabolism
  • Signal Transduction*
  • Sterol Regulatory Element Binding Protein 1 / metabolism

Substances

  • Interleukin-6
  • PPAR alpha
  • Receptors, Interleukin-6
  • Sterol Regulatory Element Binding Protein 1
  • Methionine
  • Alanine Transaminase
  • Choline