Abstract
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 language | English (US) |
---|---|
Pages (from-to) | 45-52 |
Number of pages | 8 |
Journal | Journal of Endotoxin Research |
Volume | 2 |
Issue number | 1 |
DOIs | |
State | Published - Feb 1995 |
ASJC Scopus subject areas
- Microbiology
- Immunology
- Molecular Biology
- Cell Biology
- Infectious Diseases