The iNOS Gene

However, NO also appears to play an important protective role in the body via immune cell function. When challenged with foreign antigens, 1 cells (see Chapter 55) respond by synthesizing NO. Inhibition of NOS and knockout of the iNOS gene can markedly impair the protective response to injected parasites in animal models. 

In an other hand, NO inhibits iNOS expression. When NO provokes the p53 accumulation, this one could in return inhibit iNOS gene transcription [154], Repression is observed in DLD-1 cells (human colon carcinoma) or Calu 6 cells (human pulmonary carcinoma) which express wild type p53. High NO concentration leads to p53 nitrosylation and inhibits the repression [114]. The wild type but not the mutated or the nitrosylated protein binds the iNOS gene promoter. Moreover, exogeneous NO produced by NO donors can inhibit NFkB activity in whole cells and in acellular preparation [155-157]. Those results have been confirmed in endothelial cells in which NO produced by eNOS inhibits NFkB activity and iNOS gene transcription [158], The inhibition can be explain in parts by NFkB sub-unit p50 nitrosylation [155], but also by its cytoplasmic inhibitor protein IxBa stabilisation (IkB proteins functionally retain NF-... 

Human iNOS has recently been found in immunostimulated hepatocytes and chondrocytes (Geller et al., 1993 Palmer et al., 1993). Interestingly, the activity of human iNOS appears to be calcium dependent. The gene for the human iNOS is of approximately 37 kb and contains 26 exons and 25 introns, with transcriptional initiation sites similar to those of murine iNOS. The iNOS gene is localized on chromosome 17 (Chartrain et al.,... 

Evidence is increasing that neurons are able to express iNOS in response to proper stimulation and that endogenously produced NO leads to cell death by necrotic or apoptotic mechanisms (Heneka et al. 1998). Transcriptional activation of the iNOS gene in astrocytes occurs upon incubation with several pro-inflammatory cytokines, either alone or in various combinations (Simmons and Murphy 1994). 

Caspase inhibition has been observed after exposure to NO in normal and tumor cells by chemical NO donors or NO generated by endogenous NOS. NO inhibited caspase-3, -8, and -9 activity by S-nitrosation in the catalytic site of the enzyme in cells. Moreover, transfection of the iNOS gene inhibited TNF-a-induced activation of caspase in cells (Torok et al. 2002). 

Worthington, J., Robson, T., O Keeffe, M., and Hirst, D.G. (2002). Tumour cell radiosensitization using constitutive (CMV) and radiation inducible (WAFl) promoters to drive the iNOS gene a novel suicide gene therapy. Gene Ther. 9, 263-269. 

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