Transforming growth factor-beta stimulation of lung fibroblast prostaglandin E2 production

Transforming growth factor-beta (TGF beta) stimulated the production of total protein, collagen, and fibronectin by normal human lung fibroblasts. The stimulatory response was maximal at 100 pM TGF beta and reversed toward control at higher concentrations. Inhibition of fibroblast prostaglandin (PG) synthesis enhanced TGF beta-induced stimulation of total protein, collagen, and fibronectin production and reversed the negative slope of the dose-response curve at high concentrations of TGF beta. Determination of the steady-state levels of Types I and III procollagens and fibronectin mRNAs employing specific cDNA probes demonstrated that inhibition of fibroblast PG production increased the stimulatory effect of TGF beta on the levels of these transcripts. Exogenous PGE2 abrogated the stimulatory effects of TGF beta. These findings suggest that fibroblast stimulation by TGF beta may be down-regulated by endogenous PG synthesized in response to TGF beta. This notion was supported by the demonstration that TGF beta markedly stimulated fibroblast PGE2 production. These results indicate that TGF beta-induced stimulation of fibroblast PGE2 production may be an autoregulatory control mechanism to limit the effects of TGF beta on connective tissue protein synthesis.