Effect of itraconazoles on the production of pro-inflammatory substances in mouse macrophage-like cells.
METHODS
Synthetic triazoles are widely used for the treatment of fungal 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 μg/ml). Itraconazoles dose-dependently increased the production of prostaglandin E₂ (PGE₂) and tumor necrosis factor-α (TNF-α) without affecting the production of interleukin-1β (IL-1β) and nitric oxide (NO). LPS treatment significantly enhanced the production of NO, PGE₂, TNF-α and IL-1β. The addition of itraconazoles to LPS-stimulated RAW264.7 cells significantly reduced the production of NO, but rather enhanced the production of PGE₂, TNF-α and IL-1β. 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.


CONCLUSIONS
These data suggest that itraconazoles regulate NO and other pro-inflammatory substances differently in activated macrophages.
Department of Oral Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama 350-8550, Japan.
Takao
T
Kato
Norio
N
Horie
Ken
K
Hashimoto
Kazue
K
Satoh
Tetsuo
T
Shimoyama
Tadayoshi
T
Kaneko
Kaoru
K
Kusama
Hiroshi
H
Sakagami
D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D015232:Dinoprostone / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D017964:Itraconazole / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000935:Antifungal Agents; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C084794:hydroxyitraconazole; D017964:Itraconazole; D009569:Nitric Oxide; D015232:Dinoprostone