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Up Regulation, TGFbeta1 expression leads to Activation, Stellate cells
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
Transforming growth factor beta 1 (TGF-β1) is the most potent fibrogenic factor for epatic stellate cells (HSCs). In response to TGF-β1, HSCs activate into myofibroblast-like cells, producing type I, III and IV collagen, proteoglycans like biglycan and decorin, glycoproteins like laminin, fibronectin, tenascin and glycosaminoglycan.  In the further course of events activated HSCs themselves express TGF-β1. TGF-β1 induces its own mRNA to sustain high levels in local sites of liver injury. The effects of TGF-β1 are mediated by intracellular signalling via Smad proteins. Smads 2 and 3 are stimulatory whereas Smad 7 is inhibitory. Smad1/5/8, MAP kinase and PI3 kinase are further signalling pathways in different cell types for TGF-β1 effects.  Concomitant with increased TGF-β production, HSC increase production of collagen. Connective tissue growth factor (CTGF) is a profibrogenic peptide induced by TGF-β, that stimulates the synthesis of collagen type I and fibronectin and may mediate some of the downstream effects of TGF-β. It is upregulated during activation of HSC, suggesting that its expression is another determinant of a fibrogenic response to TGF-β . During fibrogenesis, tissue and blood levels of active TGF-β are elevated and overexpression of TGF-β1 in transgenic mice can induce fibrosis. Additionally, experimental fibrosis can be inhibited by anti-TGF-β treatments with neutralizing antibodies or soluble TbRs (TGF-β receptors) .
Evidence Supporting this KER
Uncertainties and Inconsistencies
There are no uncertainties that TGF-b1 activates HSCs.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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