Two Triazole Anti-fungal Drugs Modify IgE-dependent Cytokine Release from Human Lung Tissue Explants
RATIONALE: Triazole antifungal drugs are widely used to treat allergic bronchopulmonary aspergillosis but may have other beneficial effects. We have examined the effects of pretreating human lung tissue with Itraconazole or Fluconazole on the IgE-dependent release of TNFÃƒÅ½Ã‚Â± and IL-10. METHODS: Human lung tissue was obtained from patients undergoing lung surgery at Southampton General Hospital (n = 10, 4F/6 M), dissected into 2-3 mm3 explants and incubated with either DMSO control or either Itraconazole (10-0.001Ãƒâ€˜Ã‚956;g/ml) or Fluconazole (100-0.01Ãƒâ€˜Ã‚956;g/ml) for one hour. The tissue was then stimulated with either buffer control or 100Ãƒâ€˜Ã‚956;g/ml anti-IgE for 24hrs. TNFÃƒÅ½Ã‚Â± and IL-10 released into the supernatant was measured by ELISA and values corrected for tissue weight. RESULTS: Neither Itraconazole and Fluconazole caused significant release of TNFÃƒÅ½Ã‚Â± or IL-10 in unstimulated tissue however the highest concentration of both drugs caused a significant increase in the IgE-mediated release of both TNFÃƒÅ½Ã‚Â± and IL-10 from the tissue. 100Ãƒâ€˜Ã‚956;g/ml Fluconazole increased TNFÃƒÅ½Ã‚Â± release from 34.1Ãƒâ€˜Ã‚Â±18.0 pg/mg tissue in the absence of drug to 63.7Ãƒâ€˜Ã‚Â±36.1 pg/mg tissue while Itraconazole increased release to 68.3Ãƒâ€˜Ã‚Â±26.5 pg/mg tissue. Intriguingly there was evidence that lower doses of both drugs inhibited IgE-dependent TNFÃƒÅ½Ã‚Â± release. We also examined the effect of both drugs on IL-10 release and found a significant increase in anti-IgE induced IL-10 release at the highest concentrations of both Itraconazole and Fluconazole but no evidence for inhibition at the lower concentrations. CONCLUSIONS: Both Itraconzole and Fluconazole modulate the release of TNFÃƒÅ½Ã‚Â± and IL-10 from human lung tissue and may modify inflammatory processes by a mechanism distinct from their anti-fungal actions.
Full conference title:
American Academy of Allergy Asthma & Immunology