Blockade of interleukin-6 signaling enhances hepatic steatosis but improves liver injury in methionine choline-deficient diet-fed mice.
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.
Yamaguchi
Kanji
K
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Itoh
Yoshito
Y
Yokomizo
Chihiro
C
Nishimura
Takeshi
T
Niimi
Toshihisa
T
Fujii
Hideki
H
Okanoue
Takeshi
T
Yoshikawa
Toshikazu
T
D000410:Alanine Transaminase / Q000097:blood / Q000378:metabolism; D000818:Animals; D002794:Choline / Q000009:adverse effects / Q000378:metabolism; D002796:Choline Deficiency / Q000150:complications* / Q000378:metabolism; D004032:Diet / Q000009:adverse effects*; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D005796:Genes; D015850:Interleukin-6 / Q000009:adverse effects / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000009:adverse effects / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000009:adverse effects / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
D015850:Interleukin-6; D047493:PPAR alpha; D019947:Receptors, Interleukin-6; D051780:Sterol Regulatory Element Binding Protein 1; D008715:Methionine; D000410:Alanine Transaminase; D002794:Choline