Inhibition of myofibroblast apoptosis by transforming growth factor β1

Fibroblast differentiation to the myofibroblast phenotype is associated with alpha-smooth-muscle actin (alpha-SMA) expression and regulated by cytokines. Among these, transforming growth factor (TGF)beta(1) and interleukin (IL)-1 beta can stimulate and inhibit myofibroblast differentiation, respectively. IL-1 beta inhibits alpha-SMA expression by inducing apoptosis selectively in myofibroblasts via induction of nitric oxide synthase (inducible nitric oxide synthase [iNOS]). Because TGF-P is known to inhibit iNOS expression, this study was undertaken to see if this cytokine can protect against IL-1 beta-induced myofibroblast apoptosis. Rat lung fibroblasts were treated with IL-IP and/or TGF-P, and examined for expression of alpha-SMA, iNOS, and the apoptotic regulatory proteins bar and bcl-2. The results show that TGF-beta(1) caused a virtual complete supression of IL-1 beta-induced iNOS expression while preventing the decline in alpha-SMA expression or the myofibroblast subpopulation. TGF-beta(1) treatment also completely suppressed the IL-1 beta-induced apoptosis in myofibroblasts. IL-1 beta-induced apoptosis was associated with a significant decline in expression of the antiapoptotic protein bcl-2, which was prevented by concomitant TGF-beta(1) treatment. The level of the proapoptotic protein bar, however, was not significantly altered by either cytokine. These data suggest that TGF-beta(1) inhibits IL-1 beta-induced poptosis in myofibroblasts by at least two mechanisms, namely, the suppression of iNOS expression and the prevention of a decline in bcl-2 expression. Thus, TGF-beta(1) may be additionally important in fibrosis by virtue of this novel ability to promote myofibroblast survival by preventing the myotrbroblast from undergoing apoptosis. Zhang, H.-Y., and S. H. Phan. 1999. Inhibition of myofibroblast apoptosis by transforming growth factor beta(1).