title: Differential regulation of cytokine production in lipopolysaccharide tolerance in mice.
abstract: We investigated the pattern of down-regulation of cytokine production in endotoxin (lipopolysaccharide [LPS]) tolerance. A 4-day treatment with LPS (35 micrograms 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 micrograms 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-1 alpha, using the same treatment schedule as that for LPS. Whereas IL-6 had no effect, IL-1 alpha 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.
authors.affiliation: Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Erroi
authors.forename: G
authors.initials: G
authors.lastname: Fantuzzi
authors.forename: M
authors.initials: M
authors.lastname: Mengozzi
authors.forename: M
authors.initials: M
authors.lastname: Sironi
authors.forename: S F
authors.initials: SF
authors.lastname: Orencole
authors.forename: B D
authors.initials: BD
authors.lastname: Clark
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: A
authors.initials: A
authors.lastname: Isetta
authors.forename: P
authors.initials: P
authors.lastname: Gnocchi
authors.forename: M
authors.initials: M
authors.lastname: Giovarelli
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D004361:Drug Tolerance; D005260:Female; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D051379:Mice; D008815:Mice, Inbred Strains; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D013755:Tetradecanoylphorbol Acetate