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‐γ (IFN‐γ) was a potent stimulus of N=O synthesis by KC. Treatment with LPS and IFN‐γ also induced significant production of prostaglandin E2 (PGE2), thromboxane B2 (TBX2), tumor necrosis factor a (TNF‐ α), interleukin‐1 (IL‐1), and IL‐6. Inhibition of N=O synthesis by the L‐arginine analogue N G ‐monomethyl‐L‐ar‐ ginine (NMA) resulted in a further increase of PGEs, TXBs, and EL‐6 but not BL‐l and TNF‐α 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‐γ 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 PGE 2 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 PGE 2 and TXB 2 production through diminished PGH 2 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./