Endogenous nitric oxide inhibits the synthesis of cyclooxygenase products and interleukin-6 by rat Kupffer cells

Abstract

Macrophage production of nitric oxide (.N = O) leads to considerable alterations of vital metabolic pathways in various target cells. The present study tested whether .N = O synthesis by Kupffer cells (KCs), the resident macrophages of the liver, interferes with the secretory function of these cells. As in other macrophage-type cells, the combination of lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) was a potent stimulus of .N = O synthesis by KC. Treatment with LPS and IFN-gamma also induced significant production of prostaglandin E2 (PGE2), thromboxane B2 (TBX2), tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), and IL-6. Inhibition of .N = O synthesis by KC. Treatment with LPS and IFN-gamma also induced significant production of prostaglandin E2 (PGE2), thromboxane B2 (TBX2), tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), and IL-6. Inhibition of .N = O synthesis by the L-arginine analogue of NG-monomethyl-L-arginine (NMA) resulted in a further increase of PGE2, TXB2, and IL-6 but not IL-1 and TNF-alpha production, indicating specific inhibitory effects of endogenous .N = O synthesis on the secretory activity of KCs. PGE2 production was most sensitive to the suppressive effect of .N = O and increased 24 h after stimulation with LPS and IFN-gamma from 16.3 +/- 4.9 ng/10(6) KCs without NMA to 94.3 +/- 17.9 ng/10(6) KCs with NMA. This effect of NMA was reversed by a 10-fold increase of the L-arginine concentration. No recovery of PGE2 production was seen when .N = O synthesis was blocked after 24 h. NMA treatment increased cyclooxygenase activity more than threefold, suggesting that .N = O inhibits PGE2 and TXB2 production through diminished PGH2 availability. .N = O synthesis did not significantly affect total protein synthesis or viability of the KCs. These results show that .N = O influences the production of specific inflammatory mediators by KCs.

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

“…Salvemini et al (34) have shown that injection of iNOS inhibitors into a rodent air pouch model (carrageenan-induced) blocked both iNOS and COX-2 activity in areas of inflammation. Our studies, in contrast, are similar to the studies by Stadler et al (35) and Swierkosz et al (36) that indicate that endogenous NO inhibits the synthesis of COX products as observed in rodent Kupffer cells and macrophages, respectively. This controversy may be due to the tissue-specific expression of NOS/COX-2 in various cell types, the difference in the pathophysiology of normal and OA-affected chondrocytes, and the influence of various other mediators in the microenvironment of the cartilage that may influence the production of NO and PGE 2 .…”

Upregulation of COX-2 During Cardiac Allograft Rejection

“…27 The co-induction of COX-2 and iNOS has also been observed in studies in vitro of rat vascular smooth muscle cells, 28,29 glomerular mesangial cells, 7 murine macrophages, 30 rat islets of Langerhans, 31 human endothelial cells, 32 articular chondrocytes, 33 and rabbit hepatocytes 34 incubated with endotoxin and/or cytokines but not in similar studies of human fetal cell fibroblasts 6 or bovine aortic endothelial cells. 35 Proinflammatory cytokines known to be synthesized and released by T lymphocytes and macrophages during cardiac allograft rejection are probably responsible for induction of COX-2 in this situation.…”

“…In cultured bovine endothelial cells, NO or NO donor drugs have been shown to inhibit PGI 2 release by bradykinin (COX-1) 39 and to inhibit COX-2 induction and activity in rat Kupffer cells. 34 In contrast, however, NO and NO donor drugs have been shown to stimulate COX-1 and COX-2 activity in endotoxin-activated murine macrophages 6 and in vascular smooth muscle cells 28 and human endothelial cells. 39,40 Similarly, in the hydronephrotic model of renal inflammation, 22 in air-pouchinduced inflammation, 24 there is evidence that NO augments the activity of COX-1 and COX-2, leading to enhanced synthesis of prostaglandins.…”

The chemical biology of nitric oxide: Implications in cellular signaling

“…Several studies have indicated that in murine and human models these upper level fluxes of NO can be achieved in tissue. Inhibition of P450 and COX-2 have provided evidence that locally, high levels of NO can be achieved by inflamed liver cells [90][91][92] . Nitric oxide mediated inhibition of P450 may have important consequence under inflammatory conditions 93, 94 .…”