Abstract
Current evidence suggests that regulation of extracellular matrix (ECM) accumulation by fibrogenic transforming growth factor (TGF)-β and platelet-derived growth factor (PDGF) signals involves different mechanisms in acute and chronic liver injuries, even though hepatic stellate cells (HSC) are the principal effecter in both cases. As a result of chronic liver damage, HSC undergo progressive activation to become myofibroblasts (MFB)-like cells. Our current review will discuss the differential regulation of TGF-β signaling between HSC and MFB in vitro and in vivo. Smad proteins, which convey signals from TGF-β receptors to the nucleus, have intermediate linker regions between conserved Mad-homology (MH) 1 and MH2 domains. TGF-β type I receptor and Ras-associated kinases differentially phosphorylate Smad2 and Smad3 to create COOH-terminally (C), linker (L), or dually (L/C) phosphorylated (p) isoforms. After acute liver injury, TGF-β and PDGF synergistically promote collagen synthesis in the activated HSC via pSmad2L/C and pSmad3L/C pathways. To avoid unlimited ECM deposition, Smad7 induced by TGF-β negatively regulates the fibrogenic TGF-β signaling. In contrast, TGF-β and PDGF can transmit the fibrogenic pSmad2L/C and mitogenic pSmad3L signals in MFB throughout chronic liver injury, because Smad7 cannot be induced by the pSmad3L pathway. This lack of Smad7 induction might lead to constitutive fibrogenesis in MFB, which eventually develop into accelerated liver fibrosis.
Highlights
Current evidence suggests that regulation of extracellular matrix (ECM) accumulation in acute and chronic liver injuries involves different mechanisms, even though hepatic stellate cells (HSC) are the principal effecter in both cases (Friedman, 2010)
Responsiveness of ECM production to transforming growth factor-β (TGF-β) is transient in the process of tissue repair such as liver regeneration after acute liver injury (Date et al, 1998, 2000), suggesting that some regulatory mechanisms for the Transforming growth factor (TGF)-β signal are present in the activated HSC
To elucidate how cytostatic TGF-β signaling in HSC takes on collagen-producing features within inflammatory microenvironments during acute liver injury, we focus on the Smad pathway investigating localization of pSmad2L/C and pSmad3L/C in chemically injured rat livers
Summary
Current evidence suggests that regulation of extracellular matrix (ECM) accumulation in acute and chronic liver injuries involves different mechanisms, even though hepatic stellate cells (HSC) are the principal effecter in both cases (Friedman, 2010). On the other hand, plateletderived growth factor (PDGF) through tyrosine kinase receptor is the most powerful mitogen for HSC, and promotes liver fibrosis (Pinzani, 1999). Within inflammatory microenvironment, both TGF-β and PDGF are secreted by platelets and Kupffer cells (Pinzani and Macias-Barragan, 2010). Responsiveness of ECM production to TGF-β is transient in the process of tissue repair such as liver regeneration after acute liver injury (Date et al, 1998, 2000), suggesting that some regulatory mechanisms for the TGF-β signal are present in the activated HSC. Antagonistic Smad acts in opposition to R-Smads and www.frontiersin.org
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