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Characterization and regulation of insulin‐like growth factor binding proteins in human hepatic stellate cells
Author(s) -
Gentilini Alessandra,
Feliers Denis,
Pinzani Massimo,
Woodruff Kathleen,
Abboud Sherry
Publication year - 1998
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/(sici)1097-4652(199802)174:2<240::aid-jcp11>3.0.co;2-g
Subject(s) - hepatic stellate cell , autocrine signalling , growth factor , insulin like growth factor binding protein , paracrine signalling , biology , endocrinology , medicine , insulin like growth factor , platelet derived growth factor , cell growth , cell culture , transforming growth factor beta , platelet derived growth factor receptor , transforming growth factor , binding protein , microbiology and biotechnology , receptor , biochemistry , gene , genetics
Cultured hepatic stellate cells (HSCs), the cell type primarily involved in the progression of liver fibrosis, secrete insulin‐like growth factor‐I (IGF‐I) and IGF binding protein (IGFBP) activity. IGF‐I exerts a mitogenic effect on HSCs, thus potentially contributing to the fibrogenic process in an autocrine fashion. However, IGF‐I action is modulated by the presence of specific IGFBPs that may inhibit and/or enhance its biologic effects. Therefore, we examined IGFBP‐1 through IGFBP‐6 mRNA and protein expression in HSCs isolated from human liver and activated in culture. Regulation of IGFBPs in response to IGF‐I and other polypeptide growth factors involved in the hepatic fibrogenic process was also assessed. RNase protection assays and ligand blot analysis demonstrated that HSCs express IGFBP‐2 through IGFBP‐6 mRNAs and release detectable levels of IGFBP‐2 through IGFBP‐5. Because IGF‐I, platelet‐derived growth factor‐BB (PDGF‐BB), and transforming growth factor‐β (TGF‐β) stimulate HSC proliferation and/or matrix production, we tested their effect on IGFBPs released by HSCs. IGF‐I induced IGFBP‐3 and IGFBP‐5 proteins in a time‐dependent manner without an increase in the corresponding mRNAs. IGFBP‐4 protein levels decreased in response to IGF‐I. TGF‐β stimulated IGFBP‐3 mRNA and protein but decreased IGFBP‐5 mRNA and protein. In contrast, PDGF‐BB failed to regulate IGFBPs compared with controls. Recombinant human IGFBP‐3 (rhIGFBP‐3) was then tested for its effect on IGF‐I‐induced mitogenesis in HSCs. rhIGFBP‐3 inhibited IGF‐I‐stimulated DNA synthesis in a dose‐dependent manner, with a peak effect observed at 25 nM IGFBP‐3. Because TGF‐β is highly expressed in cirrhotic liver tissue, we determined whether IGFBP‐3 mRNA expression is increased in liver biopsies obtained from patients with an active fibroproliferative response due to viral‐induced chronic active hepatitis. In the majority of these samples, IGFBP‐3 mRNA was increased compared with normal controls. These findings indicate that human HSCs, in their activated phenotype, constitutively produce IGFBPs. IGF‐I and TGF‐β differentially regulate IGFBP‐3, IGFBP‐4, and IGFBP‐5 expression, which, in turn, may modulate the in vitro and in vivo action of IGF‐I. J. Cell. Physiol. 174:240–250, 1998. © 1998 Wiley‐Liss, Inc.