Role of macrophage-derived nitric oxide in endotoxin lethality in mice

M. J. Parmely, S. Y. Hao, D. C. Morrison, J. L. Pace

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4 Scopus citations


Endotoxic lipopolysaccharides (LPS) mediate lethality in mice by a complex inflammatory process involving the production of multiple mediators, including tumor necrosis factor-α (TNF-α) and nitric oxide (NO). The present study had two objectives: (i) to determine the extent to which TNF-α contributes to the induction of NO production by mouse macrophages activated with LPS in vitro; and (ii) to assess the contribution of macrophage-derived NO to the pathogenesis of endotoxin shock in mice. The studies reported here show that the synthetic adenyl carbocyclic nucleoside 9-[(1S,3R)-cis-cyclopentan-3-ol]adenine (cPA) inhibited TNF-α, but not NO, production by thioglycollate-elicited peritoneal macrophages that were activated with either LPS alone, LPS + interferon-γ (IFN-γ) or IFN-γ + TNF-α. The expression of cytoplasmic TNF-α in LPS + IFN-γ-activated cells was similarly inhibited by cPA, whereas the appearance of inducible NO synthase was unaffected by the compound. Of significance, pretreatment of mice with a single injection of cPA protected the animals against subsequent LPS challenge in two models of endotoxin lethality. These results suggest that macrophage-derived NO, induced by LPS, may not be an essential mediator of the lethal effects of endotoxin. Further, the results of these studies suggest that TNF-α-induced NO production by tissue macrophages also may not be an essential contributing factor in the pathogenesis of lethality induced by endotoxin in mice.

Original languageEnglish (US)
Pages (from-to)45-52
Number of pages8
JournalJournal of Endotoxin Research
Issue number1
StatePublished - Feb 1995

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Toxicology


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