Inhibitor kB and Nuclear Factor kB in Granulocyte-Macrophage Colony-Stimulating Factor Antagonism of Dexamethasone Suppression of the Macrophage Response to Aspergillus fumigatus Conidia
Author:
Jung-Hyun Choi, Elmer Brummer, Young Jun Kang, Patricia P. Jones, and David A. Stevens
Date: 2 May 2006
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 B (IB) induction by DEX and is opposed by acceleration of IB degradation by GM-CSF with or without conidia stimulation, with corresponding effects on translocation and activation of nuclear factor B (NF-B). 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. IB degradation and NF-B activation were assessed by Western blot. Results. Macrophages stimulated with conidia alone increased NF-B translocation. DEX increased IB levels in cytoplasm and blocked translocation of NF-B to the nucleus in unstimulated and conidia-stimulated macrophages. Conversely, GM-CSF decreased IB levels. GM-CSF reversed the effect of DEX on IB levels. NF-B levels were minimal in DEX-treated macrophage nuclear extracts, compared with those from GM-CSF-treated and GM-CSF plus DEX-treated macrophages. Conclusion. GM-CSF can reverse the DEX immunosuppressive effect by enhancing IB degradation and promoting NF-B translocation. This would allow macrophage production of proinflammatory cytokines, facilitating resistance to aspergillosis
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