title: Transforming growth factor-β (TGF-β)-mediated connective tissue growth factor (CTGF) expression in hepatic stellate cells requires Stat3 signaling activation.
abstract: In fibrotic liver, connective tissue growth factor (CTGF) is constantly expressed in activated hepatic stellate cells (HSCs) and acts downstream of TGF-β to modulate extracellular matrix production. Distinct from other cell types in which Smad signaling plays major role in regulating CTGF production, TGF-β stimulated CTGF expression in activated HSCs is only in part dependent on Smad3. Other signaling molecules like MAPKs and PI3Ks may also participate in this process, and the underlying mechanisms have yet to be clarified. In this study, we report involvement of Stat3 activation in modulating CTGF production upon TGF-β challenge in activated HSCs. Stat3 is phosphorylated via JAK1 and acts as a critical ALK5 (activin receptor-like kinase 5) downstream signaling molecule to mediate CTGF expression. This process requires de novo gene transcription and is additionally modulated by MEK1/2, JNK, and PI3K pathways. Cell-specific knockdown of Smad3 partially decreases CTGF production, whereas it has no significant influence on Stat3 activation. The total CTGF production induced by TGF-β in activated HSCs is therefore, to a large extent, dependent on the balance and integration of the canonical Smad3 and Stat3 signaling pathways.
authors.affiliation: From the Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany,; the Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany,; the Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Liu
authors.affiliation: From the Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Meyer
authors.affiliation: the Department of General, Visceral Surgery and Transplantation, University Hospital Tübingen, 72076 Tübingen, Germany, and; the Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: the Department of General, Visceral Surgery and Transplantation, University Hospital Tübingen, 72076 Tübingen, Germany, and.
authors.forename: Silvio
authors.initials: S
authors.lastname: Nadalin
authors.affiliation: the Department of General, Visceral Surgery and Transplantation, University Hospital Tübingen, 72076 Tübingen, Germany, and.
authors.forename: Alfred
authors.initials: A
authors.lastname: Königsrainer
authors.affiliation: From the Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
authors.forename: Honglei
authors.initials: H
authors.lastname: Weng
authors.affiliation: From the Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany,. Electronic address: steven.dooley@medma.uni-heidelberg.de.
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.affiliation: the Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands,. Electronic address: p.ten_dijke@lumc.nl.
authors.forename: Peter
authors.initials: P
authors.lastname: Ten Dijke
mesh_terms: D002461:Cell Line, Transformed; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: C526317:CCN2 protein, human; C497790:SMAD3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D019869:Phosphatidylinositol 3-Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: ERK; Jak Kinase; Jun N-terminal Kinase (JNK); Liver Fibrosis; MAP Kinases (MAPKs); PI 3-kinase (PI3K); SMAD Transcription Factor