Abstract

In the present study, we determined the interactive effects of ethanol and transforming growth factor β-3 (TGF-β3) on basic fibroblast growth factor (bFGF) release from folliculostellate (FS) cells and the role of the mitogen-activated protein kinase (MAPK) pathway in this interaction. We found that TGF-β3 and ethanol alone increased release of bFGF from FS cells, but together they showed markedly increased levels of bFGF compared with the individual effect. Ethanol and TGF-β3 alone moderately increased activation of MAPK p44/42, but together they produced marked activation of MAPK p44/42. TGF-β3 alone increased the activation of smad2. Ethanol did not activate smad2 or alter TGF-β3 activation of smad2. Pretreatment of FS cells with a mitogen-activated protein kinase kinase 1/2 inhibitor or with a protein kinase C (PKC) inhibitor suppressed the TGF-β3 and ethanol actions on MAPK p44/42 activation and bFGF release. Ethanol and TGF-β3, either alone or in combination, increased the levels of active Ras. Furthermore, the MAPK p44/42 activation by TGF-β3 and ethanol was blocked by overexpression of Ras N17, a dominant negative mutant of Ras p21. These data suggest that the PKC-activated Ras-dependent MAPK p44/42 pathway is involved in the cross talk between TGF-β3 and ethanol to increase bFGF release from FS cells.