Nitric oxide suppresses human T lymphocyte proliferation through IFN-γ-dependent and IFN-γ-independent induction of apoptosis

Human normal and malignant T cells cease to proliferate, down-modulate Bcl-2 expression, and undergo apoptosis when cultured in the presence of NO-donor compounds (sodium nitroprusside and NOC12) for 48 h, At 72 h, cells that evade apoptosis start to proliferate again, overexpress both chains of the IFN-gamma R, and thus become susceptible to apoptosis in the presence of IFN-gamma. By contrast, in the presence of IFN-gamma, no apoptosis, but an increase of proliferation was displayed by control cultures of T cells not exposed to NO and not overexpressing IFN-gamma R chains. The NO-induced cell surface overexpression of IFN-gamma R chains did not affect the transduction of IFN-gamma-mediated signals, as shown by the expression of the transcription factor IFN regulatory factor I (IRF-1). However, transduction of these signals was quantitatively modified, because IFN-gamma induces enhanced levels of caspase-1 effector death in NO-treated cells, These findings identify NO as one of the environmental factors that critically govern the response of T cells to IFN-gamma By inducing the overexpression of IFN-gamma R chains, NO decides whether IFN-gamma promotes cell proliferation or the induction of apoptosis.