Differential regulation of cytokine production in lipopolysaccharide tolerance in mice

A. Erroi, G. Fantuzzi, M. Mengozzi, M. Sironi, S. F. Orencole, B. D. Clark, C. A. Dinarello, A. Isetta, P. Gnocchi, M. Giovarelli, P. Ghezzi

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We investigated the pattern of down-regulation of cytokine production in endotoxin (lipopolysaccharide [LPS]) tolerance. A 4-day treatment with LPS (35 μg per mouse) was followed by a challenge on day 6 with one more injection of LPS. Circulating tumor necrosis factor (TNF) and interleukin-6 (IL-6) could not be induced (>99% inhibition) by LPS in LPS-tolerant mice; colony-stimulating factor (CSF) was also down-regulated by more than 95%, whereas interferon (IFN) and IL-1 syntheses were only partially inhibited. To study the mechanism of cytokine down-regulation in tolerance, we attempted to reverse the tolerant state by pretreatment with phorbol 12-myristate 13- acetate (PMA) (4 μg per mouse) 10 min before the LPS challenge. PMA completely restored IL-6 production and partially that of CSF. PMA had no effect on IFN production and inhibited the induction of IL-1. TNF production was also not restored by PMA. To investigate the role of endogenously produced cytokines in the development of LPS tolerance, we administered IL- 6, TNF, or IL-1α, using the same treatment schedule as that for LPS. Whereas IL-6 had no effect, IL-1α or TNF induced partial tolerance to LPS in terms of inhibition of LPS-stimulated TNF and IL-6 production. However, a full LPS- tolerant state could not be induced by administration of recombinant cytokines, suggesting the existence of additional mechanisms, such as a loss of LPS receptors or changes in release of soluble binding proteins.

Original languageEnglish
Pages (from-to)4356-4359
Number of pages4
JournalInfection and Immunity
Issue number10
Publication statusPublished - 1993

ASJC Scopus subject areas

  • Immunology


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