THE EFFECTS OF THE ANTIFUNGAL AZOLES ITRACONAZOLE, FLUCONAZOLE, KETOCONAZOLE AND MICONAZOLE ON CYTOKINE GENE-EXPRESSION IN HUMAN LYMPHOID-CELLS

The antifungal azole drugs itraconazole (itra; R51,211), fluconazole (flu; UK-49,858), ketoconazole (keto) and miconazole (mico) have been investigated for their suppressive influence on the gene expression of the immunoregulatory cytokines IL2, IL4, IL9, GM-CSF, TNF-alpha, IFN-gamma, as well as both chains of the IL2 receptor in human PBMC and of the cytokines in the human keratinocyte cell line HaCat 17.5. The results obtained in Northern blot analysis were compared with the effects of the established immunosuppressant drug CSA and the new immunosuppressive drug FK 506, as well as the cytokine TGF-beta, which is also immunosuppressive. While 1-mu-g/ml CSA and 0.1-mu-g/ml FK 506 completely suppressed PHA-stimulated accumulation of mRNA for IL2, IL,4, IL-9, GM-CSF, TNF-alpha and IFN-gamma in PBMC, flu, keto and TGF-beta failed to inhibit any (except TNF-alpha blocked by TGF-beta). Itra and mico did suppress accumulation of mRNA, but unlike CSA and FK 506, only at high doses (10-mu-g/ml) and after extended incubation (24 h). None of the drugs nor TGF-beta suppressed the expression of the IL.2R-alpha and IL2R-beta genes or TNF-alpha-stimulated cytokine gene expression in keratinocytes. Itra and mico, 1 mg/ml (achievable serum level), caused only slight inhibition of the cytokines in PBMC after 6 and 24 h of incubation. These results demonstrate that the mode of action of the azoles is different from CSA and FK 506. In the case of itra and mico the observed inhibition of cytokine gene expression might not be the primary immunosuppressive mode of action: it is more likely that the azoles act, at least partly through a different, as vet unknown, mechanism.