title: Endotoxin tolerance after severe injury and its regulatory mechanisms.
abstract: OBJECTIVE
  To study the responsiveness of peripheral blood mononuclear cells to lipopolysaccharide (LPS) after severe trauma and its regulatory mechanisms.
  
  
  METHODS
  The release of proinflammatory reacting cytokines (tumor necrosis factor-alpha, interleukin (IL)-1 beta, IL-6, IL-8, interferon (IFN)-gamma) into whole blood from 12 patients on day 1, 5, 10, and 14 after severe trauma (Injury Severity Score, 39.3 +/- 2.8 points) and 10 healthy volunteers was studied after stimulation with LPS, concanavalin A, phorbol myristate acetate (PMA), and the addition of recombinant IFN-gamma.
  
  
  RESULTS
  Trauma caused a significant reduction of LPS and concanavalin A induced release of inflammation activating cytokines into whole blood, including IFN-gamma. However, the diminished release of proinflammatory cytokines could be increased with recombinant IFN-gamma or even attenuated after stimulation of peripheral blood mononuclear cells with the protein kinase C activator PMA.
  
  
  CONCLUSIONS
  Trauma leads to reduced responsiveness of blood monocytes to LPS and a decreased secretion of proinflammatory reacting lymphokines. Because activation of the protein kinase C pathway with PMA or the addition of IFN-gamma significantly increased cytokine response, endotoxin tolerance is not caused by inhibition of protein synthesis, but to disturbances in the signal transduction pathway and its regulating mediators.
authors.affiliation: Division of Trauma Surgery, University Hospital Zurich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Keel
authors.forename: N
authors.initials: N
authors.lastname: Schregenberger
authors.forename: U
authors.initials: U
authors.lastname: Steckholzer
authors.forename: U
authors.initials: U
authors.lastname: Ungethüm
authors.forename: J
authors.initials: J
authors.lastname: Kenney
authors.forename: O
authors.initials: O
authors.lastname: Trentz
authors.forename: W
authors.initials: W
authors.lastname: Ertel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016207:Cytokines / Q000096:biosynthesis*; D004926:Escherichia coli / Q000276:immunology; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009104:Multiple Trauma / Q000276:immunology*; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma