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Am. J. Respir. Cell Mol. Biol., Volume 21, Number 6, December, 1999 658-665

Inhibition of Myofibroblast Apoptosis by Transforming Growth Factor beta 1

Hong-Yu Zhang and Sem H. Phan

Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan

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)-1beta can stimulate and inhibit myofibroblast differentiation, respectively. IL-1beta inhibits alpha -SMA expression by inducing apoptosis selectively in myofibroblasts via induction of nitric oxide synthase (inducible nitric oxide synthase [iNOS]). Because TGF-beta is known to inhibit iNOS expression, this study was undertaken to see if this cytokine can protect against IL-1beta -induced myofibroblast apoptosis. Rat lung fibroblasts were treated with IL-1beta and/or TGF-beta 1 and examined for expression of alpha -SMA, iNOS, and the apoptotic regulatory proteins bax and bcl-2. The results show that TGF-beta 1 caused a virtually complete suppression of IL-1beta -induced iNOS expression while preventing the decline in alpha -SMA expression or the myofibroblast subpopulation. TGF-beta 1 treatment also completely suppressed the IL-1beta -induced apoptosis in myofibroblasts. IL-1beta -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 bax, however, was not significantly altered by either cytokine. These data suggest that TGF-beta 1 inhibits IL-1beta -induced apoptosis 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 myofibroblast from undergoing apoptosis.




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