title: Involvement of STAT3-regulated hepatic soluble factors in attenuation of stellate cell activity and liver fibrogenesis in mice.
abstract: Glycoprotein 130 (gp130)/signal transducer and activator of transcription 3 (STAT3) signaling in hepatocytes controls a variety of physiological and pathological processes including liver regeneration, apoptosis resistance and metabolism. Recent research has shed light on the importance of acute phase proteins (APPs) regulated by hepatic gp130/STAT3 in host defense through suppression of innate immune responses during systemic inflammation. To examine whether these STAT3-regulated soluble factors directly affect liver fibrogenic responses during liver injury, hepatocyte-specific STAT3 knockout (L-STAT3 KO) mice and control littermates were subjected to bile duct ligation (BDL) and examined 10 days later. In contrast to controls, L-STAT3 KO mice failed to produce APPs, such as serum amyloid A and haptoglobin, after BDL. Whereas L-STAT3 KO mice displayed similar levels of cholestasis, inflammatory cell infiltration and regeneration in the liver, they developed exacerbated liver injury and fibrosis with significant increases in expression of alpha-smooth muscle actin and type I collagen genes. In vitro experiments revealed that attenuated expression of APPs in primary hepatocytes isolated from L-STAT3 KO mice with IL-6 exposure, compared to wild-type hepatocytes. The cultured supernatant from IL-6-treated wild-type hepatocytes inhibited expression of alpha-smooth muscle actin and type I collagen genes in activated hepatic stellate cells (HSCs), whereas this did not occur with the supernatant from IL-6-treated knockout hepatocytes or with control medium. In conclusion, the absence of STAT3 in hepatocytes leads to exacerbation of liver fibrosis during cholestasis. Soluble factors released from hepatocytes, dependent on STAT3, collectively play a protective role in liver fibrogenesis through an inhibitory effect on activated HSCs.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Shigekawa
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kodama
authors.forename: Hayato
authors.initials: H
authors.lastname: Hikita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shimizu
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyagi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hosui
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ishida
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kanto
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
mesh_terms: D000209:Acute-Phase Proteins / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D002779:Cholestasis / Q000150:complications; D018450:Disease Progression; D006242:Haptoglobins / Q000096:biosynthesis* / Q000235:genetics; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000494:pharmacology; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D000685:Serum Amyloid A Protein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000209:Acute-Phase Proteins; D006242:Haptoglobins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D000685:Serum Amyloid A Protein; C494087:Stat3 protein, mouse