Am. J. Respir. Cell Mol. Biol.,
Volume 21, Number 6, December, 1999 658-665
Inhibition of Myofibroblast Apoptosis by Transforming Growth Factor 
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 
-smooth-muscle actin (-SMA)
expression and regulated by cytokines. Among these, transforming growth factor (TGF)-
1 and interleukin
(IL)-1 can stimulate and inhibit myofibroblast differentiation, respectively. IL-1 inhibits -SMA expression by inducing apoptosis selectively in myofibroblasts via induction of nitric oxide synthase (inducible
nitric oxide synthase [iNOS]). Because TGF- is known to inhibit iNOS expression, this study was undertaken to see if this cytokine can protect against IL-1-induced myofibroblast apoptosis. Rat lung fibroblasts
were treated with IL-1 and/or TGF-1 and examined for expression of -SMA, iNOS, and the apoptotic
regulatory proteins bax and bcl-2. The results show that TGF-1 caused a virtually complete suppression
of IL-1-induced iNOS expression while preventing the decline in -SMA expression or the myofibroblast subpopulation. TGF-1 treatment also completely suppressed the IL-1-induced apoptosis in myofibroblasts. IL-1-induced apoptosis was associated with a significant decline in expression of the antiapoptotic protein bcl-2, which was prevented by concomitant TGF-1 treatment. The level of the proapoptotic
protein bax, however, was not significantly altered by either cytokine. These data suggest that TGF-1 inhibits IL-1-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-1 may be additionally
important in fibrosis by virtue of this novel ability to promote myofibroblast survival by preventing the
myofibroblast from undergoing apoptosis.
