Antipsoriatic effects of avarol-3′-thiosalicylate are mediated by inhibition of TNF-α generation and NF-κB activation in mouse skin
Antipsoriatic effects of avarol-3′-thiosalicylate are mediated by inhibition of TNF-α generation and NF-κB activation in mouse skin
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DOI：
10.1038/sj.bjp.0707394
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发表时间：
2007-10-01
影响因子：
7.3
通讯作者：
Terencio, M. C.
中科院分区：
文献类型：
--
作者：
Amigo, M.;Paya, M.;Terencio, M. C.
背景与目的：Avarol是一种海洋倍半萜对苯二酚，具有抗炎、抗银屑病作用。本研究的目的是评估衍生物阿伐洛尔-3 '-硫代水杨酸酯（TA）对与银屑病发病机制相关的一些炎症参数的体外和体内药理学行为。使用人中性粒细胞和单核细胞以及人角质形成细胞系HaCaT来研究TA对氧化应激、花生四烯酸途径肿瘤坏死因子-α（TNF-α）释放和核因子-κ B（NF-κ B）活化。所有这些参数也确定在体内使用酵母多糖诱导的小鼠气囊模型和12-O-十四烷酰基佛波醇-13-乙酸酯（TPA）诱导的小鼠表皮hyperplasia model.Key结果：TA显示在人类中性粒细胞和次黄嘌呤/黄嘌呤氧化酶测定的抗氧化性能。该化合物以浓度依赖性方式减少活化白细胞中白三烯B-4、前列腺素E-2和TNF-α的产生。在小鼠气囊模型中口服和袋内给予TA产生了所有这些炎症介质的剂量依赖性减少。TA还抑制HaCaT角质形成细胞分泌型磷脂酶A（2）活性和NF-κ B DNA结合。在TPA诱导的小鼠表皮增生中，局部施用TA减少皮肤中的水肿、白细胞浸润、类花生酸水平和TNF-α。此外，白细胞介素（IL）-1 β和IL-2的产生也受到抑制。最后，TA也能够抑制NF-κ B B核转位invivo.Conclusions和影响：TA抑制银屑病皮肤炎症反应中上调的几个关键生物标志物，这种化合物可能是一种有前途的抗银屑病剂。
Background and purpose: Avarol is a marine sesquiterpenoid hydroquinone with anti-inflammatory and antipsoriatic properties. The aim of this study was to evaluate the in vitro and in vivo pharmacological behaviour of the derivative avarol-3'-thiosalicylate (TA) on some inflammatory parameters related to the pathogenesis of psoriasis.Experimental approach: Human neutrophils and monocytes as well as the human keratinocyte cell line HaCaT were used to study the effect of TA on oxidative stress, the arachidonic acid pathway, tumour necrosis factor-alpha (TNF-alpha) release and nuclear factor-kappa B (NF-kappa B) activation. All these parameters were also determined in vivo using the zymosan induced mouse air pouch model and the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced mouse epidermal hyperplasia model.Key results: TA showed antioxidant properties in human neutrophils and in the hypoxanthine/xanthine oxidase assay. This compound reduced, in a concentration-dependent manner, leukotriene B-4, prostaglandin E-2 and TNF-alpha production in activated leukocytes. Oral and intrapouch administration of TA in the mouse air pouch model produced a dose-dependent reduction of all these inflammatory mediators. TA also inhibited secretory phospholipase A(2) activity and NF-kappa B DNA-binding in HaCaT keratinocytes. In TPA-induced mouse epidermal hyperplasia, topical administration of TA reduced oedema, leukocyte infiltration, eicosanoid levels and TNF-alpha in skin. In addition, interleukin (IL)-1 beta and IL-2 production were also inhibited. Finally, TA was also capable of suppressing NF-kappa B nuclear translocation in vivo.Conclusions and implications: TA inhibited several key biomarkers up-regulated in the inflammatory response of psoriatic skin and this compound could be a promising antipsoriatic agent.