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Inhibition of Inducible Nitric-Oxide Synthase Protects Human T Cells from Hypoxia-Induced Apoptosis

Armed Forces Radiobiology Research Institute and Departments of Radiation Biology, Pharmacology, and Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland (J.G.K.); Department of Internal Medicine, Washington Hospital Center, Washington, DC (S.K.); and Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, Maryland (X.L., Y.L.)

Sodium cyanide-induced chemical hypoxia triggers a series of biochemical alterations leading to apoptosis in many cell types, including T cells. It is known that chemical hypoxia promotes inducible nitric-oxide synthase (iNOS) gene transcription by activating its transcription factors. To determine whether iNOS and NO production are responsible for chemical hypoxia-induced apoptosis, we exposed human Jurkat T cells to sodium cyanide in the presence or absence of iNOS inhibitors. We found that iNOS expression is necessary for hypoxia-induced lipid peroxidation and leukotriene B₄ generation. The inhibition of iNOS limited T-cell apoptosis by decreasing the activity of caspase-3 without affecting the expression of Fas/Apo-1/CD95 on the surface membrane of T cells. These data suggest iNOS-mediated NO produced endogenously in the T cell alters overall T-cell function and results in apoptosis. Proper control of iNOS expressed in the T cell may represent a useful approach to immunomodulation.

Address correspondence to: Dr. Juliann G. Kiang, Armed Forces Radiobiology Research Institute, Bldg. 46, Room 2423, 8901 Wisconsin Ave., Bethesda, MD 20889-5603. E-mail: kiang{at}afrri.usuhs.mil