Interaction between conidia, lung macrophages, immunosuppressants, proinflammatory cytokines and transcriptional regulation.
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.
Brummer
E
E
Division of Infectious Diseases, Department of Medicine, Santa Clara Valley Medical Center, 751 South Bascom Ave., San Jose, CA 95128-2699, USA.
Choi
J H
JH
Stevens
D A
DA
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
D016207:Cytokines; D007166:Immunosuppressive Agents; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor