title: Potent suppression of IL-12 production from monocytes and dendritic cells during endotoxin tolerance.
abstract: Endotoxin tolerance, the down-regulation of a subset of endotoxin-driven responses after an initial exposure to endotoxin, may provide protection from the uncontrolled immunological activation of acute endotoxic shock. Recent data suggest, however, that the inhibition of monocyte/macrophage function associated with endotoxin tolerance can lead to an inability to respond appropriately to secondary infections in survivors of endotoxic shock. IL-12 production by antigen-presenting cells is central to the orchestration of both innate and acquired cell-mediated immune responses to many pathogens. IL-12 has also been shown to play an important role in pathological responses to endotoxin. We therefore examined the regulation of IL-12 during endotoxin tolerance. Priming doses of lipopolysaccharide ablate the IL-12 productive capacity of primary human monocytes. This suppression of IL-12 production is primarily transcriptional. Unlike the down-regulation of TNF-alpha under such conditions, the mechanism of IL-12 suppression during endotoxin tolerance is not dependent upon IL-10 or transforming growth factor-beta, nor is IL-12 production rescued by IFN-gamma or granulocyte-macrophage colony-stimulating factor. Of note, human dendritic cells also undergo endotoxin tolerance, with potent down-regulation of IL-12 production. Endotoxin tolerance-related suppression of IL-12 production provides a likely mechanism for the anergy seen during the immunological paralysis which follows septic shock.
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD, USA. ckarp@welchlink.welch.jhu.edu
authors.forename: C L
authors.initials: CL
authors.lastname: Karp
authors.forename: M
authors.initials: M
authors.lastname: Wysocka
authors.forename: X
authors.initials: X
authors.lastname: Ma
authors.forename: M
authors.initials: M
authors.lastname: Marovich
authors.forename: R E
authors.initials: RE
authors.lastname: Factor
authors.forename: T
authors.initials: T
authors.lastname: Nutman
authors.forename: M
authors.initials: M
authors.lastname: Armant
authors.forename: L
authors.initials: L
authors.lastname: Wahl
authors.forename: P
authors.initials: P
authors.lastname: Cuomo
authors.forename: G
authors.initials: G
authors.lastname: Trinchieri
mesh_terms: D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018664:Interleukin-12