Inhibitor kappaB and nuclear factor kappaB in granulocyte-macrophage colony-stimulating factor antagonism of dexamethasone suppression of the macrophage response to Aspergillus fumigatus conidia

• Published in: The Journal of infectious diseases Vol. 193; no. 7; pp. 1023 - 1028
• Main Authors: Choi, Jung-Hyun, Brummer, Elmer, Kang, Young Jun, Jones, Patricia P, Stevens, David A
• Format: Journal Article
• Language: English
• Published: United States 01.04.2006
• Subjects: Animals; Anti-Inflammatory Agents - antagonists & inhibitors; Anti-Inflammatory Agents - pharmacology; Aspergillosis - immunology; Aspergillosis - microbiology; Aspergillus fumigatus - immunology; Blotting, Western; Cell Line; Cells, Cultured; Dexamethasone - antagonists & inhibitors; Dexamethasone - pharmacology; Granulocyte-Macrophage Colony-Stimulating Factor - physiology; Macrophages - immunology; Male; Mice; NF-kappa B p50 Subunit - analysis; NF-kappa B p50 Subunit - metabolism; Proteins - metabolism; Proteins - physiology; Spores, Fungal - immunology
• ISSN: 0022-1899; 1537-6613

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). 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. 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. 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.