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

J. Stadler, B. G. Harbrecht, M. Di Silvio, R. D. Curran, M. L. Jordan, R. L. Simmons, T. R. Billiar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

234 Scopus citations


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 N(G)-monomethyl-L-arginine (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.

Original languageEnglish
Pages (from-to)165-172
Number of pages8
JournalJournal of Leukocyte Biology
Issue number2
StatePublished - 1993
Externally publishedYes


  • L-arginine
  • cytokines
  • prostaglandins


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