Abstract
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.
Footnotes
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This work was supported by Armed Forces Radiobiology Research Institute RAB2CF and Department of Defense RAMII STO C (both to J.G.K.).
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ABBREVIATIONS: PMN, polymorphonuclear neutrophil; LT, leukotriene; iNOS, inducible nitric-oxide synthase; ONOO-, peroxynitrite; l-NIL, l-N6-(1-iminoethyl)-lysine; LNNA, Nω-nitro-l-arginine; cNOS, constitutive nitric oxide synthase; PG, prostaglandin; HSP, heat shock protein; HSP-70i, 70-kDa inducible heat shock protein; HIF, hypoxia-inducible factor; siRNA, small interfering RNA; PBS, phosphate-buffered saline; i, inducible; MDA, malondialdehyde; ANOVA, analysis of variance; CON, control; HX, hypoxia; lipo, Lipofectamine reagent.
- Received August 27, 2007.
- Accepted December 13, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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