Molecular regulation of the human inducible nitric oxide synthase (iNOS) gene

In critically ill patients, the human inducible nitric oxide synthase (iNOS ) gene is expressed in nearly every organ and has been shown to be associat ed with the refractory hypotension of septic and hemorrhagic shock. The mol ecular regulation of iNOS expression is complex and occurs at multiple site s in the gene expression pathway. Work in our laboratory has demonstrated t hat a combination of cytokines synergistically activate iNOS expression, wh ich has resulted in the cloning of the first human iNOS gene from cytokine- stimulated hepatocytes. In addition, we have demonstrated that iNOS express ion is transcriptionally regulated and that the functional promoter element s are located upstream of -4.7 kilobases (kb) within a unique enhancer regi on containing four functional nuclear factor kappa B elements. These result s contrast markedly with the murine iNOS promoter, where only 1.0 kb of 5'- flanking sequence is required for lipopolysaccharide and cytokine responsiv eness. Furthermore, numerous mechanisms have evolved to down-regulate iNOS expression. By elucidating these mechanisms, therapeutic strategies to gove rn iNOS expression may be developed.