title: Glucocorticoids Have Opposing Effects on Liver Fibrosis in Hepatic Stellate and Immune Cells.
abstract: Liver fibrosis is a reversible wound-healing process that is protective in the short term, but prolonged fibrotic responses lead to excessive accumulation of extracellular matrix components that suppresses hepatocyte regeneration, resulting in permanent liver damage. Upon liver damage, nonparenchymal cells including immune cells and hepatic stellate cells (HSCs) have crucial roles in the progression and regression of liver fibrosis. Here, we report differential roles of the glucocorticoid receptor (GR), acting in immune cells and HSCs, in liver fibrosis. In the carbon tetrachloride hepatotoxin-induced fibrosis model, both steroidal and nonsteroidal GR ligands suppressed expression of fibrotic genes and decreased extracellular matrix deposition but also inhibited immune cell infiltration and exacerbated liver injury. These counteracting effects of GR ligands were dissociated in mice with conditional GR knockout in immune cells (GR(LysM)) or HSC (GR(hGFAP)): the impacts of dexamethasone on immune cell infiltration and liver injury were totally blunted in GR(LysM) mice, whereas the suppression of fibrotic gene expression was diminished in GR(hGFAP) mice. The effect of GR activation in HSC was further confirmed in the LX-2 HSC cell line, in which antifibrotic effects were mediated by GR ligand inhibition of Sma and mad-related protein 3 (SMAD3) expression. We conclude that GR has differential roles in immune cells and HSCs to modulate liver injury and liver fibrosis. Specific activation of HSC-GR without alteration of GR activity in immune cells provides a potential therapeutic approach to treatment of hepatic fibrosis.
authors.affiliation: Department of Molecular and Cellular Biology (K.H.K., J.M.L., Y.Z., D.D.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Cell Biology (J.M.L.), School of Medicine, Kyungpook National University, Daegu, Republic of Korea 41944; Integrative Molecular and Biomedical Sciences Graduate Program (Y.Z., D.D.M.), Baylor College of Medicine, Houston, Texas 77030; and Department of Pediatrics (S.H.), Baylor College of Medicine and Texas Children's Hospital, Houston, Texas 77030.
authors.forename: Kang Ho
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Molecular and Cellular Biology (K.H.K., J.M.L., Y.Z., D.D.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Cell Biology (J.M.L.), School of Medicine, Kyungpook National University, Daegu, Republic of Korea 41944; Integrative Molecular and Biomedical Sciences Graduate Program (Y.Z., D.D.M.), Baylor College of Medicine, Houston, Texas 77030; and Department of Pediatrics (S.H.), Baylor College of Medicine and Texas Children's Hospital, Houston, Texas 77030.
authors.forename: Jae Man
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Molecular and Cellular Biology (K.H.K., J.M.L., Y.Z., D.D.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Cell Biology (J.M.L.), School of Medicine, Kyungpook National University, Daegu, Republic of Korea 41944; Integrative Molecular and Biomedical Sciences Graduate Program (Y.Z., D.D.M.), Baylor College of Medicine, Houston, Texas 77030; and Department of Pediatrics (S.H.), Baylor College of Medicine and Texas Children's Hospital, Houston, Texas 77030.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Molecular and Cellular Biology (K.H.K., J.M.L., Y.Z., D.D.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Cell Biology (J.M.L.), School of Medicine, Kyungpook National University, Daegu, Republic of Korea 41944; Integrative Molecular and Biomedical Sciences Graduate Program (Y.Z., D.D.M.), Baylor College of Medicine, Houston, Texas 77030; and Department of Pediatrics (S.H.), Baylor College of Medicine and Texas Children's Hospital, Houston, Texas 77030.
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Harpavat
authors.affiliation: Department of Molecular and Cellular Biology (K.H.K., J.M.L., Y.Z., D.D.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Cell Biology (J.M.L.), School of Medicine, Kyungpook National University, Daegu, Republic of Korea 41944; Integrative Molecular and Biomedical Sciences Graduate Program (Y.Z., D.D.M.), Baylor College of Medicine, Houston, Texas 77030; and Department of Pediatrics (S.H.), Baylor College of Medicine and Texas Children's Hospital, Houston, Texas 77030.
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002460:Cell Line; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000378:metabolism; D005938:Glucocorticoids / Q000627:therapeutic use*; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005938:Glucocorticoids; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D002251:Carbon Tetrachloride