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 α (TNF- α), interleukin-1 (IL-1), and IL-6. Inhibition of •N=O synthesis by the L-arginine analogue NG-monomethyl-L-ar- ginine (NMA) resulted in a further increase of PGE2, TXB2, and IL-6 but not IL-1 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/106 KCs without NMA to 94.3 ± 17.9 ng/106 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. J. Leukoc. Biol. 53: 165–172; 1993.