REGULATION OF INDUCIBLE NITRIC-OXIDE SYNTHASE EXPRESSION BY MACROPHAGE PURINORECEPTORS AND CALCIUM

Macrophage activation is central to the progression of multiple diseas es via the release of inflammatory mediators such as cytokines and nit ric oxide. Despite the recognized overlap in the regulatory mechanisms involved in mediator production, little information exists regarding receptor-initiated signaling pathways that coordinately control multip le end points, such as tumor necrosis factor-alpha (TNF-alpha) and nit ric oxide production. In this study, the expression of inducible nitri c oxide synthase (iNOS) in macrophages is shown to be regulated by cal cium and by a purinoreceptor signaling system. The P-2Y purinoreceptor partial agonist, 2-methylthio-ATP (2-MeS-ATP), inhibits the expressio n of iNOS induced by lipopolysaccharide (LPS) plus interferon-gamma (I FN-gamma) in primary macrophages. Additionally, 2-MeS-ATP attenuates t he expression of iNOS in macrophages isolated from CD-1 mice challenge d with LPS, and it inhibits LPS-induced TNF-alpha and interleukin-1 al pha (IL-1 alpha) release, thereby preventing endotoxic death. Thus, pu rinoreceptors and calcium are likely to be critical for macrophage act ivation and the production of inflammatory mediators stimulated by LPS .