Cross-talk between cyclooxygenase and nitric oxide pathways: prostaglandin E2 negatively modulates induction of nitric oxide synthase by interleukin 1.

Abstract

The inflaatory cytokine interleukin 1,B(IL-113) induces both cyclooxygenase (COX) and nitric oxide synthase (NOS) with increases in the release of prostaglandin (PG) IL-1 and TNF increase nitric oxide (NO) release in macrophages (11, 12) and mesangial cells (13). The free radical NO has emerged as an important signal and effector molecule in mammalian physiology (11,12), including neurotransmission, vasodilation, and inflammation. NO is synthesized from the guanidino nitrogen of L-Arg by the catalytic reaction of NO synthase (NOS) (11,12,14,15 (21) and vascular endothelium (22)(23)(24). The cDNA for iNOS has also been cloned from a macrophage cell line (16-18).Thus inflammatory cytokines including IL-1 and TNF drive both COX and NOS pathways. These pathways share a number of similarities. A variety of cells and tissues that produce PGs simultaneously release NO in response to cytokines or other activators. Both of them are paracrine modulators of the cell functions and mediate intracellular signals via cyclic nucleotides (i.e., cAMP or cGMP). NO and some PGs dilate vascular smooth muscle and inhibit platelet aggregation (11,12). In addition, NOS and COX require heme as a cofactor (25-27) and have constitutive and cytokineinducible forms.Many effects of NO are mediated by cGMP. NO activates the soluble guanylate cyclase and increases a second messenger, cGMP, by binding to the heme moiety of the enzyme (11,12). However, it is likely that guanylate cyclase is not the only molecular target of NO. NO inhibits several enzymes in the mitochondrial electron transport system and aconitase in the citric acid cycle by interacting with iron-sulfur centers of these enzymes (12). Likewise, NO has been shown to stimulate COX activity possibly via the heme component, which binds to the active site of the COX enzyme (28-31). Thus, a close interaction between NOS and COX pathways has become evident. However, the effect of PGs on the NOS pathway has not been fully explored. Thus we determined the effects of COX inhibition and PGs on iNOS induction and expression in rat mesangial cells. MATERIALS AND METHODSMaterials. Human recombinant IL-1,B (50 half-maximal units/ng) and restriction enzymes were purchased from Boehringer Mannheim. Primers and cDNA [for the polymerase chain reaction (PCR)] for mouse iNOS and rat glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were from Clontech. NG-Monomethyl-L-arginine (LNMMA), aminoguanidine (AG), indomethacin (Indo), PGE2, forskolin (FSK), sulfanilamide, and naphthylethylenediamine dihydrochloride were from Sigma. A stable analogue of PGI2, carba prostacyclin, was from Cayman Chemicals (Ann Arbor, MI).

Deficient nitric oxide responsible for reduced nerve blood flow in diabetic rats: effects of L‐NAME, L‐arginine, sodium nitroprusside and evening primrose oil

“…Since evening primrose oil treatment of diabetic rats normalizes the production of prostacyclin by sciatic nerve in vitro, one possibility is that prostanoids support the activity of nitric oxide synthase. Interactions between the two have been reported (Gaillard et al, 1992;Marotta et al, 1992;Imai et al, 1993;Tetsuka et al, 1994;Swierkosz et al, 1995), but these are restricted to the inducible form of nitric oxide synthase and we have been unable to discover any effects on the constitutive form. Since the latter is likely to be the operative enzyme in our study, such interaction remains only a theoretical suggestion.…”

Lipoxygenase Products Regulate Nitric Oxide and Inducible Nitric Oxide Synthase Production in Interleukin-1.BETA. Stimulated Vascular Smooth Muscle Cells.

“…The COX inhibitor indomethacin has been shown to enhance cytokine-induced nitrite production in mesangial cells, and this effect was reversed by the replacement of PGE2, which is the main product of the COX pathway (36). This previous study thus indicated the possible involvement of prostaglandin E2 (PGE2) in the negative regulation of nitrite production.…”

Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide.

“…It was then Western blotted and probed with an anti-COX-2 mAb that binds to both murine and human COX-2, giving a signal at 72 kD. Knee articular cartilage from four separate OA-affected patients was individually placed in organ culture in triplicate (n ϭ 3) as described in These experiments demonstrate that in OA-affected cartilage, unlike in rat mesangial cells (22), inhibitors of PGE 2 synthesis or addition of exogenous PGE 2 had no significant effect on NO production. We also examined the influence of cytokines and endotoxin on COX-2 expression and the effect of endogenous NO in OA-affected cartilage.…”