Author:

Brummer E, Choi JH, Stevens DA

Date: 7 September 2006

Abstract:

The immunosuppressive effect of dexamethasone (DEX) on macrophage killing activity and cytokine production in response to Aspergillus fumigatus conidia is antagonized by granulocyte-macrophage colony-stimulating factor (GM-CSF). However, the intersection of signaling pathways and the molecular mechanism of this antagonism remain to be defined. We postulated that DEX inhibition of NF-kappaB was opposed by induction of IkappaB kinases (IKK) by GM-CSF + conidia stimulation, degradation of IkappaB, and release of nuclear factor kappa B (NF-kappaB). This hypothesis was tested using resident peritoneal macrophages from CD-1 mice and the murine macrophage RAW 264.7 cell line. Macrophages were unstimulated or stimulated with A. fumigatus conidia and simultaneously treated with DEX, GM-CSF or DEX + GM-CSF for 2 4 hours. IkappaB degradation in cytoplasmic extracts and translocation of NF-kappaB in nuclear extracts was measured by Western blot analysis. This showed GM-CSF reverses the immunosuppressive effect of DEX by enhancing the degradation of IkappaB and promoting the translocation of NF-kappaB to the nucleus. This would allow the production of proinflammatory cytokines by macrophages, facilitating resistance to A. fumigatus

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