Co-regulation between cyclo-oxygenase-2 and inducible nitric oxide synthase expression in the time-course of murine inflammation

Abstract

Many in vitro studies have used cell cultures to focus on the relationships between cyclo-oxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) isoforms. We have investigated the time-course of regulation and the role of COX-2 and iNOS in a model of experimental inflammation in mice, the air pouch injected with zymosan. This study demonstrates that there is an early acute phase (4 h) mediated mainly by eicosanoids, with high levels of prostaglandin E2 (PGE2) produced by cyclo-oxygenase-1. In addition, in the later phase (from 12 h) there is a participation of nitric oxide (NO) and PGE2 accompanied by co-induction of both iNOS and COX-2. These enzymes were detected in migrating leukocytes as well as in macrophages lining the air pouch. Administration of NS398 or indomethacin inhibited PGE2 levels and COX activity, but also nitrite levels and iNOS activity, which was accompanied by a reduction in iNOS expression. Aminoguanidine inhibited nitrite levels and iNOS activity in addition to exerting inhibitory effects on the COX pathway. Treatment of animals with dexamethasone reduced nitrite and PGE2 concentrations in air pouch exudates, as well as iNOS and COX-2 expression in migrating cells. Our results indicate that PGE2 and NO may play in vivo mutual modulatory roles in the inflammatory response caused by zymosan injection into the mouse air pouch, a suitable model to study drugs acting on those pathways.

Plant originated glycoprotein has anti-oxidative and anti-inflammatory effects on dextran sulfate sodium-induced colitis in mouse

“…Although the present investigation cannot establish the mechanism of interaction between NOS and COX activity, the possible mechanism is that inhibition of NO by GJE glycoprotein influence the COX-2 activity, thus may modulate the inflammation. Further, it is reported earlier that NO can stimulate COX activity via its reaction with heme component of the COX enzyme [31,32]. Accumulating evidence has suggested that the gene expression of iNOS and COX-2 can be also regulated by several transcription factors such as nuclear factor interleukin-6 (NF-IL6), FOS/JUN, CCAAT/enhancer-binding protein (C/EBP), and nuclear factor kappa B (NF-jB) [11,12].…”

Lipopolysaccharide-Induced Increase of Prostaglandin E2 Is Mediated by Inducible Nitric Oxide Synthase Activation of the Constitutive Cyclooxygenase and Induction of Membrane-Associated Prostaglandin E Synthase

“…Some studies suggested that COX-1 is the major source of PG during inflammation (36,37), whereas others suggested that the PGs that contribute to inflammatory responses are derived exclusively from COX-2 (11,38). Other investigators have dissected the inflammatory response in two phases: an early phase (4 h) mediated by COX-1-generated PG, and a later phase (after 12 h) mediated by COX-2-derived PG (39). Thus, both COX-1 and COX-2 synthesize PG during the inflammatory response, but the relative contribution of one or the other isoform depends on the a Results are expressed as mean Ϯ SEM.…”

Immunomodulatory Effects of Xylooligosaccharides

“…Pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6, are potentially capable of injuring host tissues to play key homeostatic functional roles (Laskin and Pendino, 1995). NO and PGE 2 are generated by the inducible isoforms of NO synthase (iNOS) and cyclooxygenase-2 (COX-2) (Posadas et al, 2000). NO is essential for host innate immune responses to pathogens, and for the regulation of other physiological functions including neurotransmission, vasodilatation, and neurotoxicity (MacMicking et al, 1997).…”