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1 September 2009 Geldanamycin Analog 17-DMAG Inhibits iNOS and Caspases in Gamma-Irradiated Human T Cells
Juliann G. Kiang, Joan T. Smith, Neil G. Agravante
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Inducible nitric oxide synthase (iNOS) expression and NO production increase after radiation exposure. We showed previously that inhibiting iNOS expression prevents hemorrhage injury; we therefore investigated whether inhibiting iNOS expression also limits radiation injury. Human Jurkat T cells were exposed to γ radiation (2, 4, 6 or 8 Gy), and cell lysates were collected for analysis at selected times afterward. Radiation exposure increased iNOS expression within 4 h postirradiation by increasing the levels of the iNOS transcription factors NF-κB and KLF6. By 24 h postirradiation cell viability was reduced. In these cells, NO production, lipid peroxidation, protein nitration, apoptosomes (formed by cytochrome c, caspase 9 and Apaf-1), and caspase 3 activity were significantly elevated, suggesting that the iNOS pathway had been activated. Treatment with the iNOS inhibitors 17-DMAG or L-NIL-6 24 h prior to irradiation limited these changes, as did treatment with iNOS siRNA to silence the iNOS gene. These results suggest radiation injury involves the iNOS pathway, and iNOS-mediated NO produced endogenously in the T cell alters overall T-cell function and results in apoptosis and cell lethality. Control of iNOS expression may represent a useful approach for protecting T cells from radiation injury.

Juliann G. Kiang, Joan T. Smith, and Neil G. Agravante "Geldanamycin Analog 17-DMAG Inhibits iNOS and Caspases in Gamma-Irradiated Human T Cells," Radiation Research 172(3), 321-330, (1 September 2009).
Received: 4 September 2008; Accepted: 1 April 2009; Published: 1 September 2009

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