Inhibition of inducible nitric-oxide synthase protects human T cells from hypoxia-induced apoptosis.
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 B(4) 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.
Kiang
Juliann G
JG
Armed Forces Radiobiology Research Institute, Bldg. 46, Room 2423, 8901 Wisconsin Ave., Bethesda, MD 20889-5603, USA. kiang@afrri.usuhs.mil
Krishnan
Sandeep
S
Lu
Xinyue
X
Li
Yansong
Y
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D053148:Caspase 3 / Q000032:analysis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D000860:Hypoxia; D019169:Jurkat Cells; D007975:Leukotriene B4 / Q000032:analysis / Q000096:biosynthesis; D015227:Lipid Peroxidation / Q000187:drug effects; D008315:Malondialdehyde / Q000032:analysis; D009569:Nitric Oxide / Q000032:analysis / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D012966:Sodium Cyanide / Q000494:pharmacology; D013223:Statistics as Topic; D013601:T-Lymphocytes / Q000378:metabolism*; D013997:Time Factors; D019014:fas Receptor / Q000378:metabolism
D019014:fas Receptor; D007975:Leukotriene B4; D009569:Nitric Oxide; D008315:Malondialdehyde; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3; D012966:Sodium Cyanide