Mitogen- and stress-activated protein kinases in stellate cells of normal and fibrotic rat liver

During the development of liver fibrosis, transdifferentiation of hepatic s tellate cells into myofibroblast-like cells, proliferation of the transdiff erentiated cells and excessive synthesis of collagen are controlled by tran sforming growth factor-beta (TGF-beta). The purpose of this study was to in vestigate the involvement of mitogen- und stress-activated protein kinases in the intracellular transduction of growth factor signals in cultured stel late cells derived from both normal and fibrotic rat livers. In cultured st ellate cells derived from normal livers, TGF-beta 1 as well as bFGF and PDG F were found to induce fast activation of Ras, Raf-l, MAPK kinase (MEK) and mitogen-activated protein kinases p42 and p44 (MAPK). In stellate cells of fibrotic livers, no activation of MAPK upon stimulation of the cells by ei ther TGF-beta 1, bFGF or PDGF was observed. This is consistent with reduced MEK activities and high levels of the specific MAPK phophatases MKP-1 and MKP-2 in stellate cells of fibrotic liver compared with that of normal live r. In the cells of fibrotic livers, high activities of stress-activated pro tein kinase (SAPK) were found even in the absence of growth factors.