Histamine induces human β-defensin-3 production in human keratinocytes
Histamine induces human β-defensin-3 production in human keratinocytes
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DOI：
10.1016/j.jdermsci.2009.07.012
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发表时间：
2009-11-01
影响因子：
4.6
通讯作者：
Watanabe, Shinichi
中科院分区：
文献类型：
--
作者：
Ishikawa, Takeko;Kanda, Naoko;Watanabe, Shinichi
背景：抗菌肽人β-防御素-3 (hBD-3) 由表皮角质形成细胞产生，促进皮肤抗菌防御、炎症和伤口修复。 hBD-3 诱导肥大细胞释放组胺。我们之前表明，组胺通过HI受体激活细胞外信号调节激酶（ERK）诱导AP-1成分c-Fos的表达，从而增强人角质形成细胞中激活蛋白1（AP-1）的转录活性。目的：体外检测组胺对正常人角质形成细胞中hBD-3产生的影响。方法：通过酶联免疫吸附试验和逆转录聚合酶链检测hBD-3的产生反应。通过双荧光素酶测定分析转录活性。通过Western blotting检测蛋白质的磷酸化。结果：组胺增强角质形成细胞中hBD-3的分泌和mRNA的表达。组胺诱导的 hBD-3 产生被 H I 拮抗剂吡拉明和针对信号转导器和转录激活剂 3 (STAT3) 以及 AP-1 成分 c-Jun 和 c-Fos 的反义寡核苷酸抑制。组胺增强 STAT3 转录活性并诱导 STAT3 酪氨酸和丝氨酸磷酸化。前者被Janus激酶2（JAK2）抑制剂AG490抑制，而后者被丝裂原激活蛋白激酶激酶（MEK）抑制剂PD98059抑制；两者均被吡拉明抑制。 AG490 和 PD98059 抑制组胺诱导的 hBD-3 产生和 STAT3 活性。组胺诱导JAK2酪氨酸磷酸化，吡拉明抑制该磷酸化。结论：组胺通过H I受体通过JAK2和MEK/ERK激活STAT3和AP-1，诱导人角质形成细胞产生hBD-3。组胺可能通过 hBD-3 促进皮肤抗菌防御、炎症和伤口修复。 (C) 2009 年日本皮肤病研究学会。由爱思唯尔爱尔兰有限公司出版。保留所有权利。
Background: The antimicrobial peptide human beta-defensin-3 (hBD-3) is produced by epidermal keratinocytes, and promotes cutaneous antimicrobial defense, inflammation, and wound repair. hBD-3 induces histamine release from mast cells. We previously showed that histamine enhanced transcriptional activity of activator protein-1 (AP-1) in human keratinocytes by inducing the expression of AP-1 component c-Fos via the activation of extracellular signal-regulated kinase (ERK) through HI receptors.Objective: To examine in vitro effects of histamine on hBD-3 production in normal human keratinocytes.Methods: The hBD-3 production was examined by enzyme-linked immunosorbent assays and reverse transcription-polymerase chain reaction. The transcriptional activities were analyzed by dual luciferase assays. The phosphorylation of proteins was examined by Western blotting.Results: Histamine enhanced hBD-3 secretion and mRNA expression in keratinocytes. The histamine-induced hBD-3 production was suppressed by H I antagonist pyrilamine and antisense oligonucleotides against signal transducer and activator of transcription 3 (STAT3) and AP-1 components c-Jun and c-Fos. Histamine enhanced STAT3 transcriptional activity and induced tyrosine and serine phosphorylation of STAT3. The former was suppressed by Janus kinase 2 (JAK2) inhibitor AG490, while the latter was suppressed by mitogen-activated protein kinase kinase (MEK) inhibitor PD98059; both were suppressed by pyrilamine. AG490 and PD98059 suppressed histamine-induced hBD-3 production and STAT3 activity. Histamine induced tyrosine phosphorylation of JAK2, and pyrilamine suppressed the phosphorylation.Conclusion: It is suggested that histamine induces hBD-3 production in human keratinocytes through H I receptors by activating STAT3 and AP-1 via JAK2 and MEK/ERK. Histamine may promote cutaneous antimicrobial defense, inflammation, and wound repair through hBD-3. (C) 2009 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.