Nitric oxide suppresses human T lymphocyte proliferation through IFN-gamma-dependent and IFN-gamma-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-gammaR, 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-gammaR chains. The NO-induced cell surface overexpression of IFN-gammaR chains did not affect the transduction of IFN-gamma-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-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-gammaR chains, NO decides whether IFN-gamma promotes cell proliferation or the induction of apoptosis.
Allione
A
A
Department of Clinical Sciences, University of Turin, Orbassano, Italy.
Bernabei
P
P
Bosticardo
M
M
Ariotti
S
S
Forni
G
G
Novelli
F
F
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004306:Dose-Response Relationship, Immunologic; D006131:Growth Inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D016399:Lymphoma, T-Cell / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D010750:Phosphoproteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D017471:Receptors, Interferon / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D000096743:Interferon gamma Receptor
D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma; D009569:Nitric Oxide; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D009603:Nitroso Compounds; D010750:Phosphoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017471:Receptors, Interferon; D015375:Receptors, Interleukin-2; D000096743:Interferon gamma Receptor; C494257:IRF1 protein, human; C118603:NOC 12