Characterization of TNF-α- and IL-17A-Mediated Synergistic Induction of DEFB4 Gene Expression in Human Keratinocytes through IκBζ
Characterization of TNF-α- and IL-17A-Mediated Synergistic Induction of DEFB4 Gene Expression in Human Keratinocytes through IκBζ
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DOI：
10.1016/j.jid.2016.04.012
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发表时间：
2016-08-01
影响因子：
6.5
通讯作者：
Iversen, Lars
中科院分区：
文献类型：
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作者：
Johansen, Claus;Bertelsen, Trine;Iversen, Lars
人β-防御素2（hBD 2）是由DEFB 4基因编码的一种抗菌肽，在皮肤炎症过程中发挥重要作用。hBD 2表达受肿瘤坏死因子-α（TNF-α）和IL-17 A的协同调节;然而，其潜在的调节机制尚不清楚。本研究的目的是表征TNF-α和IL-17 A协同诱导hBD 2表达的分子机制。在培养的人角质形成细胞中，我们发现转录因子有机阳离子转运蛋白1（OCT 1）与DEFB 4启动子的组成性非诱导性结合对于IL-17 A/TNF-α介导的hBD 2协同诱导至关重要，但对于CCL 20、IL 8、IL 17 C和LCN 2的协同诱导则不然。有趣的是，用IL-17 A刺激导致核因子κ B zeta（I κ B zeta）抑制剂的p38丝裂原活化蛋白激酶依赖性积累，这是hBD 2协同诱导的必要条件。最后，用TNF-α共刺激诱导NF-κ B和激活蛋白1（AP-1）与DEFB 4启动子区域中的两个特异性位点的DNA结合。因此，我们的研究表明，两种炎症刺激是如何通过三种不同的信号通路整合到一个特定的靶基因的调节中，涉及三个特定的转录因子OCT 1，NF-κ B和AP-1以及转录辅因子I κ B ζ。这些发现在银屑病中可能是重要的，其中TNF-α和IL-17 A已被鉴定为关键的致病细胞因子。
Human beta-defensin 2 (hBD2), encoded by the DEFB4 gene, is an antimicrobial peptide playing an essential role in inflammatory processes in the skin. hBD2 expression is regulated synergistically by tumor necrosis factor-alpha (TNF-alpha) and IL-17A; however, the underlying regulatory mechanisms are unknown. The purpose of this study was to characterize the molecular mechanism by which TNF-alpha and IL-17A synergistically induce hBD2 expression. In cultured human keratinocytes we show that a constitutive noninducible binding of the transcription factor organic cation transporter 1 (OCT1) to the DEFB4 promoter is crucial for IL-17A/TNF-alpha-mediated synergistic induction of hBD2 but not the synergistic induction of CCL20, IL8, IL17C and LCN2. Interestingly, stimulation with IL-17A results in a p38 mitogen-activated protein kinase-dependent accumulation of inhibitor of nuclear factor kappa B zeta (I kappa B zeta), which is a necessity for synergistic induction of hBD2. Finally, co-stimulation with TNF-alpha induces DNA binding of NF-kappa B and activator protein 1 (AP-1) to two specific sites in the DEFB4 promoter region. Hence, our study shows how two inflammatory stimuli are integrated by three different signaling pathways into the regulation of one specific target gene involving the three specific transcription factors OCT1, NF-kappa B, and AP-1 as well as the transcriptional cofactor I kappa B zeta. These findings may be important in psoriasis, where TNF-alpha and IL-17A have been identified as key pathogenic cytokines.