title: Lung microenvironment contributes to the resistance of alveolar macrophages to develop tolerance to endotoxin*.
abstract: OBJECTIVE
  Endotoxin tolerance corresponds to reprogramming of mononuclear phagocytes after iterative encounters with toll-like receptor agonists aimed to dampen the inflammatory response. We investigated why this phenomenon cannot be observed with murine alveolar macrophages.
  
  
  METHODS
  Animal study.
  
  
  METHODS
  Research institution laboratory.
  
  
  METHODS
  rag2-/-, rag2γc-/-, cd3ε-/-, µ-/-, il-15-/-, Jα18-/-, ifnγr-/-, il-18r-/-, and wild-type mice.
  
  
  METHODS
  Alveolar macrophages were harvested from untreated mice or after injection of endotoxin. Alveolar macrophages were activated in vitro with endotoxin (lipopolysaccharide), and tumor necrosis factor production was monitored.
  
  
  RESULTS
  In contrast to monocytes or peritoneal macrophages, alveolar macrophages did not display endotoxin tolerance in an ex vivo model after injection of endotoxin. An in vivo systemic inhibition of granulocyte-macrophage colony-stimulating factor or interferon-γ allowed the induction of alveolar macrophage endotoxin tolerance, which was also observed in interferon-γ receptor-deficient mice. Using mice missing different leukocyte subsets and adoptive cell transfers, we demonstrated the involvement of B lymphocytes in interferon-γ production within the lung microenvironment and in the prevention of alveolar macrophage endotoxin tolerance. Furthermore, we demonstrated the importance of interleukin-18 in preventing alveolar macrophage endotoxin tolerance through studies of interleukin-18 messenger RNA expression in il-18r-/- mice and injection of interleukin-18 in rag2-/- and µ-/- mice.
  
  
  CONCLUSIONS
  Our results support the conclusion that at homeostasis in the lungs, constitutive expression of granulocyte-macrophage colony-stimulating factor, interleukin-18, interferon-γ and possibly interleukin-15, and a cross-talk between B lymphocytes and alveolar macrophages create a microenvironment specific to the lungs that prevents alveolar macrophages from becoming tolerant to endotoxin.
authors.affiliation: Department of Infection and Epidemiology, Unit Cytokines & Inflammation, Institut Pasteur, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Philippart
authors.forename: Catherine
authors.initials: C
authors.lastname: Fitting
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Cavaillon
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001483:Base Sequence; D060833:Cellular Microenvironment / Q000187:drug effects* / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers; D004361:Drug Tolerance; D004731:Endotoxins / Q000633:toxicity*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007372:Interferons / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects*; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction
chemical_list: D016207:Cytokines; D017931:DNA Primers; D004731:Endotoxins; D007371:Interferon-gamma; D007372:Interferons