title: IFN-γ deficiency attenuates hepatic inflammation and fibrosis in a steatohepatitis model induced by a methionine- and choline-deficient high-fat diet.
abstract: Cytokines play important roles in all stages of steatohepatitis, including hepatocyte injury, the inflammatory response, and the altered function of sinusoidal cells. This study examined the involvement of a major inflammatory cytokine, interferon-γ (IFN-γ), in the progression of steatohepatitis. In a steatohepatitis model by feeding a methionine- and choline-deficient high-fat (MCDHF) diet to both wild-type and IFN-γ-deficient mice, the liver histology, expression of genes encoding inflammatory cytokines, and fibrosis-related markers were examined. To analyze the effects of IFN-γ on Kupffer cells in vitro, we examined the tumor necrosis factor-α (TNF-α) production by a mouse macrophage cell line. Forty two days of MCDHF diet resulted in weight loss, elevated aminotransferases, liver steatosis, and inflammation in wild-type mice. However, the IFN-γ-deficient mice exhibited less extensive changes. RT-PCR revealed that the expression of tumor necrosis factor-α (TNF-α), transforming growth factor-β, inducible nitric oxide synthase, interleukin-4 and osteopontin were increased in wild-type mice, although they were suppressed in IFN-γ-deficient mice. Seventy days of MCDHF diet induced much more liver fibrosis in wild-type mice than in IFN-γ-deficient mice. The expression levels of fibrosis-related genes, α-smooth muscle actin, type I collagen, tissue inhibitor of matrix metalloproteinase-1, and matrix metalloproteinase-2, were dramatically increased in wild-type mice, whereas they were significantly suppressed in IFN-γ-deficient mice. Moreover, in vitro experiments showed that, when RAW 264.7 macrophages were treated with IFN-γ, they produced TNF-α in a dose-dependent manner. The present study showed that IFN-γ deficiency might inhibit the inflammatory response of macrophages cells and subsequently suppress stellate cell activation and liver fibrosis. These findings highlight the critical role of IFN-γ in the progression of steatohepatitis.
authors.affiliation: Division of Transplantation Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535 Japan. ri-k@ncchd.go.jp.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Luo
authors.forename: Terumi
authors.initials: T
authors.lastname: Takahara
authors.forename: Kengo
authors.initials: K
authors.lastname: Kawai
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujino
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsukada
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakae
authors.forename: Liang
authors.initials: L
authors.lastname: Zhong
authors.forename: Xiao-Kang
authors.initials: XK
authors.lastname: Li
mesh_terms: D000818:Animals; D002460:Cell Line; D002796:Choline Deficiency / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat / Q000379:methods; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000150:complications / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000172:deficiency / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D008715:Methionine; D052247:Nitric Oxide Synthase Type II
keywords: hepatic stellate cell; interferon-γ; macrophage