title: 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-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.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Santa Clara Valley Medical Center, 751 South Bascom Ave., San Jose, CA 95128-2699, USA.
authors.forename: E
authors.initials: E
authors.lastname: Brummer
authors.forename: J H
authors.initials: JH
authors.lastname: Choi
authors.forename: D A
authors.initials: DA
authors.lastname: Stevens
mesh_terms: D000818:Animals; D001232:Aspergillus fumigatus / Q000254:growth & development* / Q000472:pathogenicity; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D014158:Transcription, Genetic
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor