Department of Dermatology, Teikyo University, School of Medicine, 11-1, Kaga-2, Itabashi-Ku, Tokyo, Japan.
Immunobiology. 2011 Apr;216(4):497-504. doi: 10.1016/j.imbio.2010.08.008. Epub 2010 Sep 6.
The antimicrobial peptide human β-defensin-3 (hBD-3) is produced by epidermal keratinocytes, and exhibits broad killing activity against bacteria or fungi. Prostaglandin D(2) enhances hBD-3 production in human keratinocytes by stimulating a transcription factor, activator protein-1 via chemoattractant receptor-homologous molecule expressed on T helper 2 cells (CRTH2). Prostaglandin H(2), a precursor of prostaglandin D(2) can be converted to thromboxane A(2). Certain antimycotic drugs act on keratinocytes and modulate their production of chemokines. In this in vitro study, we examined the effects of antimycotics on hBD-3 production in human keratinocytes. Antimycotics itraconazole and terbinafine hydrochloride increased hBD-3 secretion and mRNA levels in parallel to the enhanced activity of activator protein-1, expression and phosphorylation of activator protein-1 component, c-Fos, but fluconazole was ineffective. These effects were abrogated by CRTH2 antagonist. Itraconazole and terbinafine hydrochloride increased prostaglandin D(2) release from keratinocytes and reduced the release of thromboxane B(2), a thromboxane A(2) metabolite. The conditioned medium from itraconazole or terbinafine hydrochloride-treated keratinocytes inhibited the growth of Candida albicans dependently on hBD-3. These results suggest that itraconazole and terbinafine hydrochloride may enhance c-Fos expression and phosphorylation, activator protein-1 activity and hBD-3 production by increasing prostaglandin D(2) release from keratinocytes. These antimycotic drugs may suppress thromboxane A(2) synthesis and redirect the conversion of prostaglandin H(2) towards prostaglandin D(2). The induction of hBD-3 in keratinocytes is another possible mechanism for the antimycrobial effects of these drugs, which may augment the cutaneous defense activity against infection.
人β防御素-3（hBD-3）是由表皮角质形成细胞产生的，对细菌或真菌具有广泛的杀伤活性。前列腺素 D2（PGD2）通过刺激 T 辅助 2 细胞趋化因子受体同源物表达的转录因子激活蛋白-1（AP-1）来增强人角质形成细胞中 hBD-3 的产生。前列腺素 H2（PGH2）是前列腺素 D2 的前体，可以转化为血栓烷 A2。某些抗真菌药物作用于角质形成细胞并调节其趋化因子的产生。在这项体外研究中，我们研究了抗真菌药对人角质形成细胞中 hBD-3 产生的影响。抗真菌药伊曲康唑和特比萘芬盐酸盐平行增加 hBD-3 的分泌和 mRNA 水平，与 AP-1 活性增强、AP-1 组成部分 c-Fos 的表达和磷酸化一致，但氟康唑无效。这些作用被 CRTH2 拮抗剂阻断。伊曲康唑和特比萘芬盐酸盐增加了角质形成细胞中前列腺素 D2 的释放，并减少了血栓烷 B2（血栓烷 A2 的代谢物）的释放。伊曲康唑或特比萘芬盐酸盐处理的角质形成细胞的条件培养基依赖 hBD-3 抑制白色念珠菌的生长。这些结果表明，伊曲康唑和特比萘芬盐酸盐可能通过增加前列腺素 D2 从角质形成细胞中的释放来增强 c-Fos 表达和磷酸化、AP-1 活性和 hBD-3 的产生。这些抗真菌药物可能会抑制血栓烷 A2 的合成，并使前列腺素 H2 向前列腺素 D2 的转化重新定向。角质形成细胞中 hBD-3 的诱导是这些药物抗微生物作用的另一种可能机制，它可能增强皮肤对感染的防御活性。
