It is reported that antimycotic agents are effective for the treatment of patients with atopic dermatitis (AD). We studied in vitro effects of antimycotics on T helper-1 and T helper-2 cytokine production in anti-CD3 plus anti-CD28-stimulated T cells from AD patients and normal donors. The amounts of interleukin-4 (IL-4) and IL-5 secreted by anti-CD3/CD28-stimulated T cells were higher in AD patients than in normal donors. Azole derivatives, ketoconazole, itraconazole, miconazole and non-azole terbinafine hydrochloride and tolnaftate reduced IL-4 and IL-5 secretion without altering that of IFN-gamma and IL-2 in anti-CD3/CD28-stimulated T cells from both AD patients and normal donors. The azole derivatives were more inhibitory than non-azole antimycotics. These antimycotics reduced the anti-CD3/CD28-induced mRNA expression and promoter activities for IL-4 and IL-5. The cAMP analogue dibutyryl cAMP reversed the inhibitory effects of the antimycotics on IL-4 and IL-5 secretion, mRNA expression, and promoter activities. Anti-CD3/CD28 transiently (< or = 5 min) increased intracellular cAMP in T cells, and the increase was greater in AD patients than in normal donors. The increase of cAMP by anti-CD3/CD28 correlated with IL-4 and IL-5 secretion by anti-CD3/CD28. The transient cAMP increase was suppressed by antimycotics, and azole derivatives were more suppressive than non-azoles. Azole derivatives inhibited the activity of cAMP-synthesizing adenylate cyclase while terbinafine hydrochloride and tolnaftate enhanced the activity of cAMP-hydrolyzing cyclic nucleotide phosphodiesterase in AD and normal T cells. These results suggest that the antimycotics may suppress IL-4 and IL-5 production by reducing cAMP signal, and strengthen the concept of their potential use for the suppression of T helper-2-mediated allergic reactions.