Growth hormone prevents human monocytic cells from Fas-mediated apoptosis by up-regulating Bcl-2 expression

Apoptosis and particularly Fas-mediated apoptosis has been proposed to play a key role in controlling monocyte homeostasis. We and others have documen ted the regulatory function of human growth hormone (hGH) on monocytic cell s, which prompted us to investigate the role of hGH on their response to Fa s antigen cross-linking. Using human promonocytic U937 cells constitutively producing hGH upon gene transfer and human primary monocytes cultured in t he presence of recombinant hGH, we demonstrated that hGH diminished Fas-med iated cell death by enhancing the expression of the antiapoptotic oncoprote in Bcl-2 as well as the level of bcl-2 alpha mRNA. In parallel, we establis hed that overexpression of Bcl-2 through gene transfer into normal U937 cel ls also diminished Pas-induced apoptosis. Further, as a result of Bcl-2 ove rexpression, we found that hGH greatly depressed Fas-induced activation of the cysteine protease caspase-3 (CPP32), which in turn affected the cleavag e of poly(ADP-ribose) polymerase. Altogether, these data provide evidence t hat hGH mediates its protective effect through a Bcl-2-dependent pathway, c learly a crucial step in enhanced survival of monocytic cells exposed to Fa s-induced death.