Inhibition of myofibroblast apoptosis by transforming growth factor beta(1).
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.
Zhang
H Y
HY
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Phan
S H
SH
D000199:Actins / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007375:Interleukin-1 / Q000494:pharmacology; D008168:Lung / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein
D000199:Actins; C494828:Bax protein, rat; D007375:Interleukin-1; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D051028:bcl-2-Associated X Protein; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat