Kanda Naoko, Watanabe Shinichi
Department of Dermatology, Teikyo University, School of Medicine, Tokyo, Japan.
J Invest Dermatol. 2002 Sep;119(3):590-9. doi: 10.1046/j.1523-1747.2002.01864.x.
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.
我们之前报道过，抗真菌药酮康唑可抑制特应性皮炎患者T细胞中白细胞介素-4的产生。我们在此研究了酮康唑是否可能抑制B细胞IgE类别转换。与正常供体相比，特应性皮炎患者外周血表面IgE⁻B细胞中白细胞介素-4加抗CD40诱导的IgE分泌增强，且该分泌受到酮康唑的抑制。酮康唑抑制表面IgE⁻B细胞中白细胞介素-4加抗CD40诱导的种系和成熟ε转录本。酮康唑还抑制白细胞介素-4加抗CD40诱导的人伯基特淋巴瘤Ramos细胞中种系ε启动子的激活。酮康唑诱导的种系ε启动子活性抑制需要包含CCAAT/增强子结合蛋白元件的-171/-155 bp区域以及包含Stat6和核因子κB元件的-155/-109 bp区域。酮康唑抑制白细胞介素-4加抗CD40诱导的CCAAT/增强子结合蛋白和核因子κB的增强子活性，以及CCAAT/增强子结合蛋白/Stat6或Stat6/核因子κB复合元件的增强子活性，但不改变Ramos细胞中Stat6的活性。环磷酸腺苷（cAMP）类似物可逆转酮康唑对白细胞介素-4加抗CD40诱导的IgE分泌、种系和成熟ε转录本以及ε种系启动子激活的抑制作用。白细胞介素-4加抗CD40通过激活表面IgE⁻B细胞中的cAMP合成腺苷酸环化酶来增加细胞内cAMP，且特应性皮炎患者细胞中的增加幅度大于正常供体细胞。酮康唑抑制白细胞介素-4加抗CD40诱导的表面IgE⁻B细胞中腺苷酸环化酶的激活。这些结果表明，酮康唑可能通过抑制cAMP信号来抑制白细胞介素-4加抗CD40诱导的B细胞IgE类别转换，并强调其对过敏性疾病的预防作用。
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