Lipopolysaccharide-induced increase of prostaglandin E-2 is mediated by inducible nitric oxide synthase activation of the constitutive cyclooxygenaseand induction of membrane-associated prostaglandin E synthase

NO produced by the inducible NO synthase (NOS2) and prostanoids generated b y the cyclooxygenase (COX) isoforms and terminal prostanoid synthases are m ajor components of the host innate immune and inflammatory response. Eviden ce exists that pharmacological manipulation of one pathway could result in cross-modulation of the other, but the sense, amplitude, and relevance of t hese interactions are controversial, especially in vivo. Administration of 6 mg/kg LPS to rats i.p. resulted 6 h later in induction of NOS2 and the me mbrane-associated PGE synthase (mPGES) expression, and decreased constituti ve COX (COX-1) expression. Low level inducible COX (COX-2) mRNA with absent COX-2 protein expression was observed. The NOS2 inhibitor aminoguanidine ( 50 and 100 mg/kg i.p.) dose dependently decreased both NO and prostanoid pr oduction. The LPS-induced increase in PGE(2) concentration was mediated by NOS2-derived NO-dependent activation of COX-1 pathway and by induction of m PGES. Despite absent COX-2 protein, SC-236, a putative COX-2-specific inhib itor, decreased mPGES RNA expression and PGE(2) concentration. Ketoprofen, a nonspecific COX inhibitor, and SC-236 had no effect on the NOS2 pathway. Our results suggest that in a model of systemic inflammation characterized by the absence of COX-2 protein expression, NOS2-derived NO activates COX-1 pathway, and inhibitors of COX isoforms have no effect on NOS2 or NOS3 (en dothelial NOS) pathways. These results could explain, at least in part, the deleterious effects of NOS2 inhibitors in some experimental and clinical s ettings, and could imply that there is a major conceptual limitation to the use of NOS2 inhibitors during systemic inflammation.