Biphasic regulation of NF-kappa B activity underlies the pro- and anti-inflammatory actions of nitric oxide

Expression of inducible NO synthase (iNOS) by macrophages is a prerequisite for the production of high output NO, which mediates many bactericidal and tumoricidal actions of these immune cells. The expression of iNOS in mamma lian cells is governed predominantly hy the transcription factor, NF-kappaB , which regulates the expression of many host defense proteins. In the pres ent study, we characterize a novel, biphasic effect of NO on NF-kappaB acti vity in murine macrophages. This mechanism depends on the local concentrati on of NO and enables it both to up- and down-regulate the expression of hos t defense proteins including iNOS, cyclooxygenase-2, and IL-6. This biphasi c activity of NO appears to play a pivotal role in the time course of activ ation of these immune cells and, by inference, in facilitating the initiati on of a defense response against pathogenic stimuli and in its termination to limit tissue damage. This mechanism may explain at least in part the rep orted ability of NO to act in both a pro- and anti-inflammatory manner.