title: 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 epsilon transcripts in surface IgE- B cells. Ketoconazole also inhibited interleukin-4 plus anti-CD40-induced activation of germline epsilon 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 kappaB elements were required for the ketoconazole-induced inhibition of the germline epsilon promoter activity. Ketoconazole inhibited interleukin-4 plus anti-CD40-induced enhancer activities of CCAAT/enhancer-binding protein and nuclear factor kappaB, and those of composite elements of CCAAT/enhancer-binding protein/Stat6 or of Stat6/nuclear factor kappaB, 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 epsilon transcripts, and epsilon 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.
authors.affiliation: Department of Dermatology, Teikyo University, School of Medicine, Tokyo, Japan. nmk@med.teikyo-u.ac.jp
authors.forename: Naoko
authors.initials: N
authors.lastname: Kanda
authors.forename: Shinichi
authors.initials: S
authors.lastname: Watanabe
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000328:Adult; D000935:Antifungal Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002051:Burkitt Lymphoma; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D019013:CD40 Antigens / Q000276:immunology*; D000242:Cyclic AMP / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D018095:Germ-Line Mutation / Q000276:immunology; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000187:drug effects; D007073:Immunoglobulin E / Q000276:immunology* / Q000378:metabolism; D066298:In Vitro Techniques; D015847:Interleukin-4 / Q000276:immunology*; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D000935:Antifungal Agents; D022762:CCAAT-Enhancer-Binding Proteins; D019013:CD40 Antigens; D016328:NF-kappa B; D015847:Interleukin-4; D007073:Immunoglobulin E; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D007654:Ketoconazole