期刊
ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH
卷 37, 期 11, 页码 1838-1848出版社
WILEY
DOI: 10.1111/acer.12167
关键词
TGF-beta 1; PDGF- Receptor; Proliferation; Hepatic Stellate Cells; Liver Fibrosis
资金
- Ministerio de Educacion y Cultura, Spain
- [RO1 AA09231]
- [RO1 AA10541]
Background Transforming growth factor beta 1 (TGF-1) is a pleiotropic cytokine that activates hepatic stellate cell (HSC) proliferation, but inhibits parenchymal cell proliferation. Therefore, we hypothesize that TGF-1 regulates HSC proliferation and elucidated its molecular action. MethodsIn order to elucidate the molecular mechanism whereby TGF-1 up-regulates platelet derived growth factor beta (PDGF-) receptor mRNA and induces a delayed proliferation of HSC, we used proliferation and apoptosis assays as well as RT-PCR, Western blot analysis, immunostaining, and flow cytometry in mouse and rat HSC. ResultsWe show that TGF-1 markedly induces the proliferation of mouse HSC in culture with concomitant 2.1-fold (p<0.001) stimulation in [H-3]-thymidine incorporation into cellular DNA. This induction is maximal between 24 and 36hours postcytokine exposure that is triggered by 7.6-fold (p<0.001) up-regulation of PDGF- receptor mRNA and associated increase in PDGF- receptor protein after 48hours. TGF-1-dependent HSC proliferation is mimicked by H2O2 that is inhibited by catalase, implying that TGF-1 action is mediated via reactive oxygen species. HSC proliferation is blunted by PDGF- receptor-neutralizing antibody as well as by specific inhibitors of PI3 kinase (PI3K), AKT, and p70(S6K), indicating that the action of TGF-1 involves the activation of PDGF- receptor via the PI3K/AKT/p70(S6K) signaling pathway. TGF-1 also induces a reorganization of actin and myosin filaments and cell morphology leading to the formation of palisades although their myosin and actin contents remained constant. These findings suggest that TGF-1-mediated oxidative stress causes the transdifferentiation of HSC and primes them for extracellular matrix (ECM) deposition and scar contraction. ConclusionsWe conclude that liver injury up-regulates TGF-1 that inhibits parenchymal cell proliferation, but stimulates HSC proliferation leading to the production of ECM and type I collagen resulting in fibrosis.
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