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 documented the regulatory function of human growth hormone (hGH) on monocytic cells, which prompted us to investigate the role of hGH on their response to Fas antigen cross-linking. Using human promonocytic U937 cells constitutively producing hGH upon gene transfer and human primary monocytes cultured in the presence of recombinant hGH, we demonstrated that hGH diminished Fas-mediated cell death by enhancing the expression of the antiapoptotic oncoprotein Bcl-2 as well as the level of bcl-2alpha mRNA. In parallel, we established that overexpression of Bcl-2 through gene transfer into normal U937 cells also diminished Fas-induced apoptosis. Further, as a result of Bcl-2 overexpression, we found that hGH greatly depressed Fas-induced activation of the cysteine protease caspase-3 (CPP32), which in turn affected the cleavage of poly(ADP-ribose) polymerase. Altogether, these data provide evidence that hGH mediates its protective effect through a Bcl-2-dependent pathway, clearly a crucial step in enhanced survival of monocytic cells exposed to Fas-induced death.