title: Inhibitor kappaB and nuclear factor kappaB in granulocyte-macrophage colony-stimulating factor antagonism of dexamethasone suppression of the macrophage response to Aspergillus fumigatus conidia.
abstract: BACKGROUND
  The dexamethasone (DEX) immunosuppressive effect on macrophage killing activity and cytokine production in response to Aspergillus fumigatus conidia is antagonized by granulocyte-macrophage colony-stimulating factor (GM-CSF). The molecular mechanism is unknown. We postulated that this antagonism is mediated by inhibitor kappaB (I kappaB) induction by DEX and is opposed by acceleration of I kappaB degradation by GM-CSF with or without conidia stimulation, with corresponding effects on translocation and activation of nuclear factor kappa B (NF-kappaB).
  
  
  METHODS
  We studied 2 types of cells, resident peritoneal macrophages from CD-1 mice and the murine macrophage RAW264.7 cell line. Cells were unstimulated or stimulated with conidia and simultaneously treated with DEX, GM-CSF, or DEX plus GM-CSF, for 2-4 hours. I kappaB degradation and NF-kappaB activation were assessed by Western blot.
  
  
  RESULTS
  Macrophages stimulated with conidia alone increased NF-kappaB translocation. DEX increased I kappaB levels in cytoplasm and blocked translocation of NF-kappaB to the nucleus in unstimulated and conidia-stimulated macrophages. Conversely, GM-CSF decreased I kappaB levels. GM-CSF reversed the effect of DEX on I kappaB levels. NF-kappaB levels were minimal in DEX-treated macrophage nuclear extracts, compared with those from GM-CSF-treated and GM-CSF plus DEX-treated macrophages.
  
  
  CONCLUSIONS
  GM-CSF can reverse the DEX immunosuppressive effect by enhancing I kappaB degradation and promoting NF-kappaB translocation. This would allow macrophage production of proinflammatory cytokines, facilitating resistance to aspergillosis.
authors.affiliation: California Institute for Medical Research, San Jose, USA.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Choi
authors.forename: Elmer
authors.initials: E
authors.lastname: Brummer
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Kang
authors.forename: Patricia P
authors.initials: PP
authors.lastname: Jones
authors.forename: David A
authors.initials: DA
authors.lastname: Stevens
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001228:Aspergillosis / Q000276:immunology* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000276:immunology*; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D003907:Dexamethasone / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000032:analysis / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D013172:Spores, Fungal / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D047908:Intracellular Signaling Peptides and Proteins; D052002:NF-kappa B p50 Subunit; D011506:Proteins; C454819:Nfkbid protein, mouse; C073701:Nfkb1 protein, mouse