title: Interferon-β Mediates Signaling Pathways Uniquely Regulated in Hepatic Stellate Cells and Attenuates the Progression of Hepatic Fibrosis in a Dietary Mouse Model.
abstract: The results of clinical and experimental studies suggest that type I interferons (IFNs) may have direct antifibrotic activity in addition to their antiviral properties. However, the mechanisms are still unclear; in particular, little is known about the antifibrotic activity of IFN-β and how its activity is distinct from that of IFN-α. Using DNA microarrays, we demonstrated that gene expression in TWNT-4 cells, an activated human hepatic stellate cell line, was remarkably altered by IFN-β more than by IFN-α. Integrated pathway enrichment analyses revealed that a variety of IFN-β-mediated signaling pathways are uniquely regulated in TWNT-4 cells, including those related to cell cycle and Toll-like receptor 4 (TLR4) signaling. To investigate the antifibrotic activity of IFN-β and the involvement of TLR4 signaling in vivo, we used mice fed a choline-deficient l-amino acid-defined diet as a model of nonalcoholic steatohepatitis-related hepatic fibrosis. In this model, the administration of IFN-β significantly attenuated augmentation of the area of liver fibrosis, with accompanying transcriptional downregulation of the TLR4 adaptor molecule MyD88. Our results provide important clues for understanding the mechanisms of the preferential antifibrotic activity of IFN-β and suggest that IFN-β itself, as well as being a modulator of its unique signaling pathway, may be a potential treatment for patients with hepatic fibrosis in a pathogenesis-independent manner.
authors.affiliation: 1 Pharmaceutical Research Laboratory, Toray Industries, Inc. , Kamakura, Kanagawa, Japan .
authors.forename: Rieko
authors.initials: R
authors.lastname: Shimozono
authors.affiliation: 1 Pharmaceutical Research Laboratory, Toray Industries, Inc. , Kamakura, Kanagawa, Japan .
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: 2 New Projects Development Division, Toray Industries, Inc. , Kamakura, Kanagawa, Japan .
authors.forename: Hideo
authors.initials: H
authors.lastname: Akiyama
authors.affiliation: 3 Department of Bio Research, Kamakura Techno-Science, Inc. , Kamakura, Kanagawa, Japan .
authors.forename: Saeko
authors.initials: S
authors.lastname: Funamoto
authors.affiliation: 1 Pharmaceutical Research Laboratory, Toray Industries, Inc. , Kamakura, Kanagawa, Japan .
authors.forename: Akiko
authors.initials: A
authors.lastname: Izawa
authors.affiliation: 1 Pharmaceutical Research Laboratory, Toray Industries, Inc. , Kamakura, Kanagawa, Japan .
authors.forename: Takafumi
authors.initials: T
authors.lastname: Sai
authors.affiliation: 1 Pharmaceutical Research Laboratory, Toray Industries, Inc. , Kamakura, Kanagawa, Japan .
authors.forename: Kana
authors.initials: K
authors.lastname: Kunita
authors.affiliation: 1 Pharmaceutical Research Laboratory, Toray Industries, Inc. , Kamakura, Kanagawa, Japan .
authors.forename: Mie
authors.initials: M
authors.lastname: Kainoh
authors.affiliation: 1 Pharmaceutical Research Laboratory, Toray Industries, Inc. , Kamakura, Kanagawa, Japan .
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: 4 Department of Hepatology, Graduate School of Medicine, Osaka City University , Abeno, Osaka, Japan .
authors.forename: Norifumi
authors.initials: N
authors.lastname: Kawada
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002794:Choline / Q000378:metabolism; D002796:Choline Deficiency / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005526:Food, Formulated; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism / Q000494:pharmacology; D016899:Interferon-beta / Q000378:metabolism / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016898:Interferon-alpha; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016899:Interferon-beta; D002794:Choline