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

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