Inhibitor kappaB and nuclear factor kappaB in granulocyte-macrophage colony-stimulating factor antagonism of dexamethasone suppression of the macrophage response to Aspergillus fumigatus conidia.

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 kappaB (I kappaB) induction by DEX and is opposed by acceleration of I kappaB degradation by GM-CSF with or without conidia stimulation, with corresponding effects on translocation and activation of nuclear factor kappa B (NF-kappaB).

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. I kappaB degradation and NF-kappaB activation were assessed by Western blot.

RESULTS:

Macrophages stimulated with conidia alone increased NF-kappaB translocation. DEX increased I kappaB levels in cytoplasm and blocked translocation of NF-kappaB to the nucleus in unstimulated and conidia-stimulated macrophages. Conversely, GM-CSF decreased I kappaB levels. GM-CSF reversed the effect of DEX on I kappaB levels. NF-kappaB 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 I kappaB degradation and promoting NF-kappaB translocation. This would allow macrophage production of proinflammatory cytokines, facilitating resistance to aspergillosis.

• Authors: Jung-Hyun Choi, Elmer Brummer, Young Jun Kang, Patricia P Jones, David A Stevens
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 193 Issue 7 Pg. 1023-8 (Apr 01 2006) ISSN: 0022-1899 [Print] United States
• PMID: 16518765 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• IkappaBNS protein, mouse
• Intracellular Signaling Peptides and Proteins
• NF-kappa B p50 Subunit
• Proteins
• Nfkb1 protein, mouse
• Dexamethasone
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Animals
• Anti-Inflammatory Agents (antagonists & inhibitors, pharmacology)
• Aspergillosis (immunology, microbiology)
• Aspergillus fumigatus (immunology)
• Blotting, Western
• Cell Line
• Cells, Cultured
• Dexamethasone (antagonists & inhibitors, pharmacology)
• Granulocyte-Macrophage Colony-Stimulating Factor (physiology)
• Intracellular Signaling Peptides and Proteins
• Macrophages (immunology)
• Male
• Mice
• NF-kappa B p50 Subunit (analysis, metabolism)
• Proteins (metabolism, physiology)
• Spores, Fungal (immunology)