Nitric Oxide Suppresses Human T Lymphocyte Proliferation Through IFN-γ-Dependent and IFN-γ-Independent Induction of Apoptosis

Abstract

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-γR, and thus become susceptible to apoptosis in the presence of IFN-γ. By contrast, in the presence of IFN-γ, no apoptosis, but an increase of proliferation was displayed by control cultures of T cells not exposed to NO and not overexpressing IFN-γR chains. The NO-induced cell surface overexpression of IFN-γR chains did not affect the transduction of IFN-γ-mediated signals, as shown by the expression of the transcription factor IFN regulatory factor 1 (IRF-1). However, transduction of these signals was quantitatively modified, because IFN-γ 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-γ. By inducing the overexpression of IFN-γR chains, NO decides whether IFN-γ promotes cell proliferation or the induction of apoptosis.