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Differential regulation of TGF‐β signal in hepatic stellate cells between acute and chronic rat liver injury
Author(s) -
Tahashi Yoshiya,
Matsuzaki Koichi,
Date Masataka,
Yoshida Katsunori,
Furukawa Fukiko,
Sugano Yasushi,
Matsushita Masanori,
Himeno Yasuo,
Inagaki Yutaka,
Inoue Kyoichi
Publication year - 2002
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2002.30083
Subject(s) - smad , autocrine signalling , hepatic stellate cell , r smad , paracrine signalling , smad2 protein , phosphorylation , transforming growth factor beta , liver injury , signal transduction , endocrinology , biology , medicine , microbiology and biotechnology , cancer research , receptor , growth factor , tgf alpha
During chronic liver injury, transforming growth factor β (TGF‐β) plays a prominent role in stimulating liver fibrogenesis by myofibroblast‐like cells derived from hepatic stellate cells (HSCs). On the other hand, Smad 7 was recently shown to antagonize the TGF‐β–induced activation of signal‐transducing Smads (2 and 3). In this study, we investigated the regulatory mechanisms of the TGF‐β signals in rat HSCs during acute liver injury and myofibroblasts (MFBs) during chronic liver injury, focusing on the roles of Smad 2 and antagonistic Smad 7. In acute liver injury, HSC‐derived TGF‐β increased plasminogen activator inhibitor type 1 (PAI‐1) and α2(I) procollagen (COL1A2) transcripts. Smad 2 in HSCs during liver injury and primary cultured HSCs were activated by an autocrine mechanism, because high levels of Smad 2 phosphorylation and induction of PAI‐1 transcript by TGF‐β were observed in HSCs. Thereafter, Smad 7 induced by TGF‐β negatively regulated the Smad 2 action. These results indicated that endogenous TGFβ–mediated Smad 7 in HSCs terminated the fibrotic signals mediated by signal‐transducing Smads, and might be involved in the transient response to autocrine TGF‐β signal after acute liver injury. By contrast, Smad 7 was not induced by the autocrine TGF‐β signal, and constitutive Smad 2 activation was observed in MFBs throughout chronic liver injury, although Smad 7 could inhibit the TGF‐β signal requiring Smad 2 phosphorylation by activated TGF‐β receptor in cultured MFBs. This constitutive phosphorylation of Smad 2 by endogenous TGF‐β under a low level of Smad 7 could be involved in the progression of liver fibrosis.