Signaling Events Required for Transforming Growth Factor-β Stimulation of Connective Tissue Growth Factor Expression by Cultured Human Lung Fibroblasts

It is possible that many of the fibrogenic effects of transforming growth factor-β (TGF-β) are mediated by connective tissue growth factor (CTGF). In the present work, we show that TGF-β1 produces a 5- to 6-fold increase in CTGF expression by cultured human lung fibroblasts that is due mainly to increased transcription. The half-life of CTGF mRNA is 1.96 h, consistent with its role as a cytokine. In addition to requiring Smad activity, based upon the effects of specific inhibitors, the TGF-β intracellular signaling pathway requires the activity of a phosphatidylcholine-specific phospholipase C, a protein kinase C, and one or more tyrosine kinases. It is also likely that the pathway requires a member of the Ras superfamily of small GTPases, but not trimeric G proteins. Pharmacologic inhibition of TGF-β stimulation of CTGF expression may be an effective therapeutic approach to a variety of undesirable fibrotic reactions.