ENDOGENOUS NITRIC-OXIDE INHIBITS THE SYNTHESIS OF CYCLOOXYGENASE PRODUCTS AND INTERLEUKIN-6 BY RAT KUPFFER CELLS

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 the L-arginine analogue N(G)-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.