Tetracyclines Modulate Protease-Activated Receptor 2-Mediated Proinflammatory Reactions in Epidermal Keratinocytes
Tetracyclines Modulate Protease-Activated Receptor 2-Mediated Proinflammatory Reactions in Epidermal Keratinocytes
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DOI：
10.1128/aac.01540-08
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发表时间：
2009-05-01
影响因子：
4.9
通讯作者：
Yamanishi, Kiyofumi
中科院分区：
文献类型：
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作者：
Ishikawa, Chika;Tsuda, Tatsuya;Yamanishi, Kiyofumi
除了抗生素作用外，四环素类还具有抗炎作用，这通常有利于控制炎性皮肤病。在这项研究中，我们研究了四环素（泰特）及其两种衍生物，强力霉素（DOX）和米诺环素（MIN），在正常人表皮角质形成细胞（NHEK）的蛋白酶激活受体2（PAR 2）的激活引起的白细胞介素-8（IL-8）的产生的影响。在NHEK中，由PAR 2的激动剂肽SLIGKIV-NH 2在100 μ M刺激的IL-8的产生被无细胞毒性的5和10 μ M浓度的泰特、DOX或MIN显著降低。SLIGKIV-NH 2协同增强了肿瘤坏死因子α（TNF-α）诱导的IL-8产生，而IL-8产生的协同增加被100 nM PAR 2特异性小干扰RNA抑制。它也被泰特、DOX或MIN抑制，但不被14元环大环内酯类抗生素红霉素、罗红霉素和克拉霉素抑制，这些抗生素在10 μ M时也具有抗炎活性。这些结果表明四环素类减弱角质形成细胞中的PAR 2-IL-8轴，从而有效地调节皮肤中的促炎反应。
In addition to their antibiotic effects, tetracyclines have anti-inflammatory action that is often beneficial in the control of inflammatory skin disorders. In this study, we examined the effects of tetracycline (TET) and two of its derivatives, doxycycline (DOX) and minocycline (MIN), on the production of interleukin-8 (IL-8) elicited by the activation of protease-activated receptor 2 (PAR2) in normal human epidermal keratinocytes (NHEK). In NHEK, the production of IL-8 stimulated by an agonist peptide of PAR2, SLIGKIV-NH2, at 100 mu M was significantly reduced by TET, DOX, or MIN at 5 and 10 mu M, concentrations that are noncytotoxic. The tumor necrosis factor alpha (TNF-alpha)-induced production of IL-8 was synergistically augmented by SLIGKIV-NH2, and that synergistic increase in the production of IL-8 was suppressed by 100 nM PAR2-specific small interfering RNA. It was also suppressed by TET, DOX, or MIN but not by the 14-membered-ring macrolide antibiotics erythromycin, roxithromycin, and clarithromycin, which also have anti-inflammatory activities, at 10 mu M. These results suggest that tetracyclines attenuate the PAR2-IL-8 axis in keratinocytes and thereby effectively modulate proinflammatory responses in the skin.