title: IL-13 induces connective tissue growth factor in rat hepatic stellate cells via TGF-β-independent Smad signaling.
abstract: Connective tissue growth factor (CTGF) plays a central role in stimulating extracellular matrix deposition in the liver, and hence is considered a critical mediator of TGF-β-dependent fibrogenesis. Hepatic stellate cells (HSCs) are known as the major source of CTGF in damaged liver. However, previous studies revealed that IL-13, rather than TGF-β, represents the predominant inducer of CTGF expression in HSCs. We now dissected IL-13 downstream signaling that modulates CTGF expression in HSCs. IL-13 induces a time- and dosage-dependent increase of CTGF in a TGF-β-independent manner. This process requires participation of different Smad proteins and their upstream receptor kinases (activin receptor-like kinases). Smad1 and Smad2 were identified as the key mediators of IL-13-dependent CTGF expression. Furthermore, IL-13 induces Stat6 phosphorylation in HSCs, but Stat6 was not involved in CTGF induction. Instead, the Erk1/2-MAPK pathway was found to be responsible for IL-13-induced early Smad phosphorylation and CTGF synthesis. We demonstrate that IL-13 induces CTGF expression in HSCs by activating TGF-β-independent activin receptor-like kinase/Smad signaling via the Erk-MAPK pathway rather than via its canonical JAK/Stat6 pathway. These results provide an improved new insight into the molecular mechanisms of profibrotic IL-13 activities in the liver.
authors.affiliation: Molecular Hepatology-Alcohol Associated Diseases, II. Medical Clinic Faculty of Medicine at Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Christoph
authors.initials: C
authors.lastname: Meyer
authors.forename: Alexandra
authors.initials: A
authors.lastname: Müller
authors.forename: Frank
authors.initials: F
authors.lastname: Herweck
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.forename: Roman
authors.initials: R
authors.lastname: Müllenbach
authors.forename: Peter R
authors.initials: PR
authors.lastname: Mertens
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.forename: Hong-Lei
authors.initials: HL
authors.lastname: Weng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D018793:Interleukin-13; D034741:RNA, Small Interfering; D051898:Smad1 Protein; C497400:Smad1 protein, rat; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor