Effects of radiodetoxified endotoxin on nitric oxide production in J774 macrophages and in endotoxin shock

E. Gilad, B. Zingarelli, M. O'Connor, A. L. Salzman, L. Bertók, C. Szabó

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    3 Scopus citations

    Abstract

    Radiodetoxified lipopolysaccharide (RD-LPS) is a 60Co-gamma-irradiated LPS with a modified structure, which decreases its toxic effects. To obtain a better understanding of the mechanism of the reduced toxicity of RD-LPS, here we studied the effect of RD-LPS on the regulation of nitric oxide (NO) production in vitro and in vivo. In control cells, stimulation by native LPS (10 μg/ml) induced the expression of the inducible NO synthase (iNOS) and production of NO, as measured by increase in the concentration of nitrite, breakdown product of NO. Pre-exposure of the cells for 24 h to a subthreshold concentration of RD-LPS (10 ng/ml) induced a complete desensitization to the LPS-induced NO production in comparison to control cells (P < 0.01). On the contrary, pre-exposure of the cells with native LPS (10 ng/ml) did not reduce LPS-induced NO synthesis. RD-LPS induced a smaller production of tumor necrosis factor (TNF) than native LPS, but did not induce a desensitization against subsequent LPS-induced TNF synthesis. ln in vivo studies, pretreatment of rats with repeated doses of sublethal RD-LPS (1 mg/kg/day i.p. for 4 days) inhibited increase of plasma nitrate/nitrite levels, NO production in peritoneal macrophages ex vivo and induction of lung iNOS activity, in response to a high-dose LPS challenge (15 mg/kg i.p.) given at the fifth day. Pretreatment with repeated sublethal doses of the native LPS (1 mg/kg/day i.p.) did not affect NO production in rats subjected to endotoxic shock. The results demonstrate that RD-LPS induces tolerance to the stimulatory effect of LPS on NO synthesis. Suppression of iNOS induction was only observed with RD-LPS, but not with native LPS in the models used herein. It remains to be further investigated whether suppression of iNOS induction by RD-LPS contributes to the protective effects of this compound in shock and inflammation.

    Original languageEnglish (US)
    Pages (from-to)513-519
    Number of pages7
    JournalInnate Immunity
    Volume3
    Issue number6
    DOIs
    StatePublished - Dec 1 1996

    ASJC Scopus subject areas

    • Microbiology
    • Immunology
    • Molecular Biology
    • Cell Biology
    • Infectious Diseases

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  • Cite this

    Gilad, E., Zingarelli, B., O'Connor, M., Salzman, A. L., Bertók, L., & Szabó, C. (1996). Effects of radiodetoxified endotoxin on nitric oxide production in J774 macrophages and in endotoxin shock. Innate Immunity, 3(6), 513-519. https://doi.org/10.1177/096805199600300610