Regulation by Prostaglandin E₂of Cytokine-elicited Nitric Oxide Synthesis in Rat Liver Macrophages

Abstract

Nitric oxide (NO), apart from its properties as a vasodilator, is a cytotoxic agent released from macrophages upon stimulation with immunomodulating agents such as interferon-and endotoxin.In rat Kupffer cells endotoxin causes the release of NO as well as of tumor necrosis factor-a and prostaglandin E 2 (PGE 2 ). This eicosanoid and its second messenger, cyclic AMP, have been shown to increase nitric oxide formation in Kupffer cells treated with endotoxin (Gaillard et al. (1991) Pathobiology 59, 280-283). But not only added PGE 2 but also the prostaglandin produced endogenously upon stimulation with endotoxin increases NO synthesis.Neither tumor necrosis factor-nor interleukin-1/3 stimulate NO synthesis by themselves, but together with PGE 2 they are as effective as lipopolysaccharide plus PGE 2 . To replace PGE 2 in the combination with the cytokines, however, dibutyryl cAMP has to be present in higher concentrations than with LPS. Interleukin-6 alone or in combination with PGE 2 or dibutyryl cAMP is without any effect.Anti-TNF-o! as well as anti-PGE 2 antibodies reduce the release of NO upon stimulation with LPS. Consequently, the effect of LPS on NO production seems to be in part due to the self-stimulating effect of PGE 2 and some cytokines, both produced by Kupffer cells upon LPS stimulation. Regulation der durch Cytokine ausgelösten Synthese von Stickoxid durch Prostaglandin E 2 in Makrophagen der RattenleberZusammenfassung: Neben seiner Eigenschaft als Vasodilatator ist Stickoxid ein cytotoxisches Agens, das von Makrophagen nach Anregung durch Immunmodulatoren, wie Interferon-und Endotoxin gebildet wird.Endotoxin führt in Kupffer-Zellen der Ratte zur Freisetzung sowohl von NO als auch von Tumornekrosefaktor-(TNF-a) und Prostaglandin (PG)E 2 . Es war bereits gezeigt worden, daß dieses Eikosanoid und sein "second messenger", cAMP, die Stickoxidbil-

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.…”

Host Response to Infection: the Role of CpG DNA in Induction of Cyclooxygenase 2 and Nitric Oxide Synthase 2 in Murine Macrophages

“…Eicosanoids can reduce NOS2 expression and NO production (5,10,15,16,29), and NO modulates PGE 2 formation (22,26,28,31). Stimuli that enhance NOS2 expression and NO formation may also induce COX2 expression, but the time courses for induction may differ.…”

Superoxide Prevents Nitric Oxide-Mediated Suppression of Helper T Lymphocytes: Decreased Autoimmune Encephalomyelitis in Nicotinamide Adenine Dinucleotide Phosphate Oxidase Knockout Mice

“…T he free radical NO is produced by NO synthases (NOS) 3 by converting L-arginine to L-citrulline, a process that can be inhibited by analogues of L-arginine, such as N-monomethyl-L-arginine (L-NMA). Inducible NOS (iNOS) expression is induced by LPS, TNF-␣, IFN-␥ (1), cAMP (2), IL-1, and PGE 2 (3).…”

“…Inducible NOS (iNOS) expression is induced by LPS, TNF-␣, IFN-␥ (1), cAMP (2), IL-1, and PGE 2 (3). Despite extensive knowledge about NO regulation, the role of NO in tissue inflammation is controversial, as illustrated by studies involving the animal model for multiple sclerosis, experimental allergic encephalomyelitis (EAE).…”