title: IL-12 suppression during experimental endotoxin tolerance: dendritic cell loss and macrophage hyporesponsiveness.
abstract: Endotoxin tolerance, the transient, secondary down-regulation of a subset of endotoxin-driven responses after exposure to bacterial products, is thought to be an adaptive response providing protection from pathological hyperactivation of the innate immune system during bacterial infection. However, although protecting from the development of sepsis, endotoxin tolerance also can lead to fatal blunting of immunological responses to subsequent infections in survivors of septic shock. Despite considerable experimental effort aimed at characterizing the molecular mechanisms responsible for a variety of endotoxin tolerance-related phenomena, no consensus has been achieved yet. IL-12 is a macrophage- and dendritic cell (DC)-derived cytokine that plays a key role in pathological responses to endotoxin as well as in the induction of protective responses to pathogens. It recently has been shown that IL-12 production is suppressed in endotoxin tolerance, providing a likely partial mechanism for the increased risk of secondary infections in sepsis survivors. We examined the development of IL-12 suppression during endotoxin tolerance in mice. Decreased IL-12 production in vivo is clearly multifactorial, involving both loss of CD11c(high) DCs as well as alterations in the responsiveness of macrophages and remaining splenic DCs. We find no demonstrable mechanistic role for B or T lymphocytes, the soluble mediators IL-10, TNF-alpha, IFN-alphabeta, or nitric oxide, or the NF-kappaB family members p50, p52, or RelB.
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA. Mwysocka@mail.med.upenn.edu
authors.forename: M
authors.initials: M
authors.lastname: Wysocka
authors.forename: S
authors.initials: S
authors.lastname: Robertson
authors.forename: H
authors.initials: H
authors.lastname: Riemann
authors.forename: J
authors.initials: J
authors.lastname: Caamano
authors.forename: C
authors.initials: C
authors.lastname: Hunter
authors.forename: A
authors.initials: A
authors.lastname: Mackiewicz
authors.forename: L J
authors.initials: LJ
authors.lastname: Montaner
authors.forename: G
authors.initials: G
authors.lastname: Trinchieri
authors.forename: C L
authors.initials: CL
authors.lastname: Karp
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D007108:Immune Tolerance / Q000235:genetics; D007117:Immunization, Secondary; D007274:Injections, Intraperitoneal; D016167:Integrin alphaXbeta2 / Q000096:biosynthesis; D007370:Interferon Type I / Q000172:deficiency / Q000235:genetics; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D016328:NF-kappa B / Q000172:deficiency / Q000235:genetics; D052002:NF-kappa B p50 Subunit; D009569:Nitric Oxide / Q000172:deficiency / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics
chemical_list: D016167:Integrin alphaXbeta2; D007370:Interferon Type I; D008070:Lipopolysaccharides; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; C497594:Relb protein, mouse; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D051841:Transcription Factor RelB; D018664:Interleukin-12; D009569:Nitric Oxide