Loss of TGF-beta dependent growth control during HSC transdifferentiation.
Liver injury induces activation of hepatic stellate cells (HSCs) comprising expression of receptors, proliferation, and extracellular matrix synthesis triggered by a network of cytokines provided by damaged hepatocytes, activated Kupffer cells and HSCs. While 6 days after bile duct ligation in rats TGF-beta inhibited DNA synthesis in HSCs, it was enhanced after 14 days, indicating a switch from suppression to DNA synthesis stimulation during fibrogenesis. To delineate mechanisms modulating TGF-beta function, we analyzed crosstalk with signaling pathways initiated by cytokines in damaged liver. Lipopolysaccharide and tumor necrosis factor-alpha enhanced proliferation inhibition of TGF-beta, whereas interleukin-6, oncostatin M, interleukin-1alpha, and interleukin-1beta did not. Hepatocyte growth factor (HGF) counteracted TGF-beta dependent inhibition of DNA synthesis in quiescent HSCs. Since expression of c-met is induced during activation of HSCs and HGF is overrepresented in damaged liver, crosstalk of HGF and TGF-beta contributes to loss of TGF-beta dependent inhibition of DNA synthesis in HSCs.
Purps
Oliver
O
Institute of Clinical Chemistry and Pathobiochemistry, University Hospital, RWTH-Aachen, Germany.
Lahme
Birgit
B
Gressner
Axel M
AM
Meindl-Beinker
Nadja M
NM
Dooley
Steven
S
D000818:Animals; D001652:Bile Ducts / Q000503:physiopathology / Q000601:surgery; D002454:Cell Differentiation / Q000502:physiology*; D004247:DNA / Q000096:biosynthesis; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D007728:Kupffer Cells / Q000166:cytology*; D008026:Ligation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D017228:Hepatocyte Growth Factor; D004247:DNA