Effect of Itraconazoles on the Production of Pro-inflammatory Substances in Mouse Macrophage-like Cells

Background, Materials and Methods: Synthetic triazoles are widely used for the treatment of fun gal infection. In order to understand their possible anti-inflammatory action, we investigated the effect of itraconazole and its hydroxylated derivative (hydroxyitraconazole) on the production of various pro-inflammatory substances by mouse macrophage-like RAW264.7 cells. Results: These compounds did not apparently show any growth inhibitory or stimulatory effects over a wide range of concentrations (0.2-50 mu g/ml). Itraconazoles dose-dependently increased the production of prostaglandin E-2 (PGE(2)) and tumor necrosis factor-alpha (TNF-alpha) without affecting the production of interleukin-1 beta (IL-1 beta) and nitric oxide (NO). LPS treatment significantly enhanced the production of NO, PGE(2), TNF-alpha and IL-1 beta. The addition of itraconazoles to LPS-stimulated RAW264.7 cells significantly reduced the production of NO, but rather enhanced the production of PGE(2),TNF-alpha and IL-1 beta. ESR spectroscopy demonstrated that itraconazoles did not significantly scavenge NO and superoxide anion radicals, indicating that the inhibition of NO production by itraconazoles is not due to their radical-scavenging activity. Hydroxyitraconazole was slightly more cytostatic, and more efficiently inhibited NO production, but enhanced the production of other pro-inflammatory substances. Conclusion: These data suggest that itraconazoles regulate NO and other pro-inflammatory substances differently in activated macrophages.