Transforming growth factor-beta 1-induced activation of the ERK pathway/activator protein-1 in human lung fibroblasts requires the autocrine induction of basic fibroblast growth factor.
Transforming growth factor-beta (TGF-beta) is involved in multiple processes including cell growth and differentiation. In particular, TGF-beta has been implicated in the pathogenesis of fibrotic lung diseases. In this study, we examined regulation of the mitogen-activated protein kinase pathway by TGF-beta1 in primary human lung fibroblasts. TGF-beta1 treatment resulted in extracellular signal-regulated kinase (ERK) pathway activation in a delayed manner, with maximal activity at 16 h. ERK activation occurred concomitantly with the induction of activator protein-1 (AP-1) binding, a nuclear factor required for activation of multiple genes involved in fibrosis. AP-1 binding was dependent on ERK activation, since the MEK-1 (mitogen-activated protein kinase kinase) inhibitor PD98059 inhibited TGF-beta1-induced binding. Induction of the receptor tyrosine kinase-linked growth factor, basic fibroblast growth factor (bFGF) protein expression temporally paralleled the activation of ERK/AP-1. Induction of AP-1 by TGF-beta1-conditioned medium was observed at 2 h, similar to AP-1 induction in response to exogenous bFGF. Dependence of ERK/AP-1 activation on bFGF induction was demonstrated by inhibition of TGF-beta1-induced ERK/AP-1 activation when conditioned medium from TGF-beta1-treated cells was incubated with bFGF-neutralizing antibody. Together, these results demonstrate that TGF-beta1 regulates the autocrine induction of bFGF, resulting in activation of the ERK mitogen-activated protein kinase pathway and induction of AP-1 binding.
Finlay
G A
GA
Pulmonary and Critical Care Division, Department of Medicine, Tupper Research Institute, New England Medical Center, Boston, Massachusetts 02111, USA.
Thannickal
V J
VJ
Fanburg
B L
BL
Paulson
K E
KE
D002460:Cell Line; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000235:genetics*; D005347:Fibroblasts; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D007700:Kinetics; D008168:Lung; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one