Kanda Naoko, Watanabe Shinichi
Department of Dermatology, Teikyo University School of Medicine, 11-1, Kaga-2, Itabashi-Ku, Tokyo 173-8605, Japan.
Biochem Pharmacol. 2006 Aug 14;72(4):463-73. doi: 10.1016/j.bcp.2006.05.001. Epub 2006 Jun 19.
Antimycotic agents are reported to improve cutaneous symptoms of atopic dermatitis or psoriasis vulgaris. Keratinocytes in these lesions excessively produce chemokines, CCL27, CCL2, or CCL5 which trigger inflammatory infiltrates. Tumor necrosis factor-alpha (TNF-alpha) induces production of these chemokines via activating nuclear factor-kappaB (NF-kappaB). We examined in vitro effects of antimycotics on TNF-alpha-induced CCL27, CCL2, and CCL5 production in human keratinocytes. Antimycotics ketoconazole and terbinafine hydrochloride suppressed TNF-alpha-induced CCL27, CCL2, and CCL5 secretion and mRNA expression in keratinocytes in parallel to the inhibition of NF-kappaB activity while fluconazole was ineffective. Anti-prostaglandin E2 (PGE2) antiserum or antisense oligonucleotides against PGE2 receptor EP2 or EP3 abrogated inhibitory effects of ketoconazole and terbinafine hydrochloride on TNF-alpha-induced NF-kappaB activity and CCL27, CCL2, and CCL5 production, indicating the involvement of endogenous PGE2 in the inhibitory effects. Prostaglandin H2, a precursor of PGE2 can be converted to thromboxane A2. Ketoconazole, terbinafine hydrochloride and thromboxane A2 synthase (EC 5.3.99.5) inhibitor, carboxyheptyl imidazole increased PGE2 release from keratinocytes and reduced that of thromboxane B2, a stable metabolite of thromboxane A2. Carboxyheptyl imidazole also suppressed TNF-alpha-induced NF-kappaB activity and CCL27, CCL2, and CCL5 production. These results suggest that ketoconazole and terbinafine hydrochloride may suppress TNF-alpha-induced NF-kappaB activity and CCL27, CCL2, and CCL5 production by increasing PGE2 release from keratinocytes. These antimycotics may suppress thromboxane A2 synthesis and redirect the conversion of PGH2 toward PGE2. These antimycotics may alleviate inflammatory infiltration in atopic dermatitis or psoriasis vulgaris by suppressing chemokine production.
据报道，抗真菌剂可改善特应性皮炎或寻常型银屑病的皮肤症状。这些病变中的角质形成细胞会过度产生趋化因子CCL27、CCL2或CCL5，从而引发炎症浸润。肿瘤坏死因子-α（TNF-α）通过激活核因子-κB（NF-κB）诱导这些趋化因子的产生。我们研究了抗真菌剂对人角质形成细胞中TNF-α诱导的CCL27、CCL2和CCL5产生的体外作用。抗真菌剂酮康唑和盐酸特比萘芬抑制了角质形成细胞中TNF-α诱导的CCL27、CCL2和CCL5分泌及mRNA表达，同时抑制了NF-κB活性，而氟康唑则无效。抗前列腺素E2（PGE2）抗血清或针对PGE2受体EP2或EP3的反义寡核苷酸消除了酮康唑和盐酸特比萘芬对TNF-α诱导的NF-κB活性以及CCL27、CCL2和CCL5产生的抑制作用，表明内源性PGE2参与了这些抑制作用。PGE2的前体前列腺素H2可转化为血栓素A2。酮康唑、盐酸特比萘芬和血栓素A2合酶（EC 5.3.99.5）抑制剂羧基庚基咪唑增加了角质形成细胞中PGE2的释放，并减少了血栓素A2的稳定代谢产物血栓素B2的释放。羧基庚基咪唑也抑制了TNF-α诱导的NF-κB活性以及CCL27、CCL2和CCL5的产生。这些结果表明，酮康唑和盐酸特比萘芬可能通过增加角质形成细胞中PGE2的释放来抑制TNF-α诱导的NF-κB活性以及CCL27、CCL2和CCL5的产生。这些抗真菌剂可能抑制血栓素A2的合成，并使PGH2的转化转向PGE2。这些抗真菌剂可能通过抑制趋化因子的产生来减轻特应性皮炎或寻常型银屑病中的炎症浸润。
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