THE REGULATION OF SUPEROXIDE GENERATION AND NITRIC-OXIDE SYNTHESIS BYC-REACTIVE PROTEIN

Activated macrophages utilize both reactive oxygen intermediates and r eactive oxynitrogen intermediates for defence against microbes. Howeve r, simultaneous generation of superoxide (O-2((.) over bar)) and nitri c oxide (NO) could be harmful to host cells due to the production of p eroxynitrite, nitrogen dioxide and hydroxyl radicals. Therefore, the r egulation of the production of these molecules is critical to host sur vival. During periods of inflammation or infection, the level of serum C-reactive protein (CRP) increases in many species. Human and rat CRP have been shown to bind and interact with phagocytic cells. Since man y of the interactions of CRP involve the binding to the phosphocholine ligand, we studied the role of CRP in O-2((.) over bar) and NO genera tion through the modulation of phosphatidylcholine (PC) metabolism in macrophages. This study has shown that, while rat CRP inhibited phorbo l myristate acetate- (PMA) induced release of OY by rat macrophages, C RP-treated macrophages released NO in a time- and dose-dependent manne r. CRP increased inducible nitric oxide synthase (iNOS) enzyme as well as iNOS mRNA levels in rat macrophages. Tricyclodecan-9-yl-xanthogena te (D609), an inhibitor to PC phospholipase C (PC-PLC), suppressed iNO S induction but enhanced PMA-induced release of O-2((.) over bar). The se data indicate that an increased level of CRP during periods of infl ammation may result in differential regulation of macrophage NADPH oxi dase and iNOS activity. Increased hepatic synthesis of CRP may contrib ute to the mechanism by which phagocytic cells avoid simultaneous O-2( (.) over bar) and NO synthesis, and this could possibly be mediated th rough the regulation of PC-PLC.