Interaction between conidia, lung macrophages, immunosuppressants, proinflammatory cytokines and transcriptional regulation

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-κB was opposed by induction of IκB kinases (IKK) by GM-CSF+conidia stimulation, degradation of IκB, and release of nuclear factor kappa B (NF-κB). 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. IκB degradation in cytoplasmic extracts and translocation of NF-κB in nuclear extracts was measured by Western blot analysis. This showed GM-CSF reverses the immunosuppressive effect of DEX by enhancing the degradation of IκB and promoting the translocation of NF-κB to the nucleus. This would allow the production of proinflammatory cytokines by macrophages, facilitating resistance to A. fumigatus. © 2005 ISHAM.