Ketoconazole suppresses interleukin-4 plus anti-CD40-induced IgE class switching in surface IGE negative B cells from patients with atopic dermatitis

Abstract

We previously reported that antimycotic agent ketoconazole suppressed interleukin-4 production in T cells from patients with atopic dermatitis. We herein studied if ketoconazole may suppress B cell IgE class switching. Interleukin-4 plus anti-CD40-induced IgE secretion was enhanced in peripheral blood surface IgE- B cells from atopic dermatitis patients compared to those from normal donors, and the secretion was inhibited by ketoconazole. Ketoconazole suppressed interleukin-4 plus anti-CD40-induced germline and mature e transcripts in surface IgE- B cells. Ketoconazole also inhibited interleukin-4 plus anti-CD40-induced activation of germline e promoter in human Burkitt lymphoma Ramos cells. The regions -171/-155 bp containing CCAAT/enhancer-binding protein element and -155/-109 bp containing Stat6 and nuclear factor κB elements were required for the ketoconazole-induced inhibition of the germline e promoter activity. Ketoconazole inhibited interleukin-4 plus anti-CD40-induced enhancer activities of CCAAT/enhancer-binding protein and nuclear factor κB, and those of composite elements of CCAAT/enhancer-binding protein/Stat6 or of Stat6/nuclear factor κB, but did not alter that of Stat6 in Ramos cells. cAMP analog reversed the inhibitory effects of ketoconazole on interleukin-4 plus anti-CD40-induced IgE secretion, germline and mature e transcripts, and e germline promoter activation. Interleukin-4 plus anti-CD40 increased intracellular cAMP by activating cAMP-synthesizing adenylate cyclase in surface IgE- B cells, and the increase was greater in the cells from atopic dermatitis patients than in those from normal donors. Ketoconazole suppressed interleukin-4 plus anti-CD40-induced activation of adenylate cyclase in surface IgE- B cells. These results suggest that ketoconazole may suppress interleukin-4 plus anti-CD40-induced B cell IgE class switching by inhibiting cAMP signal, and stress its prophylactic effects on allergic diseases.