NF-κB and STAT3 Inhibition as a Therapeutic Strategy in Psoriasis: In Vitro and In Vivo Effects of BTH
NF-κB and STAT3 Inhibition as a Therapeutic Strategy in Psoriasis: In Vitro and In Vivo Effects of BTH
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DOI：
10.1038/jid.2013.182
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发表时间：
2013-10-01
影响因子：
6.5
通讯作者：
Carmen Terencio, M.
中科院分区：
文献类型：
--
作者：
Andres, Rosa M.;Carmen Montesinos, M.;Carmen Terencio, M.
苯并[B]噻吩-2-基-3-溴-5-羟基-5H-呋喃-2-酮（BTH）是一种简单而有趣的合成衍生物，petrosaspongiblum M是一种从海绵中分离的天然化合物，通过抑制NF-κ B信号传导途径表现出有效的抗炎活性。在本研究中，我们报告了BTH在体外和体内对银屑病发病机制中与先天性和适应性反应相关的一些参数的药理作用。BTH通过下调正常人角质形成细胞中的NF-κ B来抑制一些关键的银屑病细胞因子如肿瘤坏死因子α、IL-8、IL-6和CCL 27的释放。此外，它损害信号转导和转录激活因子3（STAT 3）磷酸化和易位到细胞核，导致角质形成细胞增殖减少。这些结果在两种银屑病小鼠模型中得到了体内证实：由12-O-十四酰基佛波醇-13-乙酸酯诱导的表皮增生和咪喹莫特诱导的皮肤炎症模型。在这两种情况下，局部施用BTH通过抑制NF-κ B和STAT 3磷酸化来防止皮肤浸润和增生。我们的研究结果证实了这两种转录因子在皮肤炎症中的关键作用，如银屑病，并强调了小分子作为治疗这种皮肤病的治疗剂的潜力，BTH是未来药物研究的潜在候选者。
Benzo[b]thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one (BTH) is a simple and interesting synthetic derivative of petrosaspongiolide M, a natural compound isolated from a sea sponge with demonstrated potent anti-inflammatory activity through inhibition of the NF-kappa B signaling pathway. In the present study, we report the in vitro and in vivo pharmacological effect of BTH on some parameters related to the innate and adaptive response in the pathogenesis of psoriasis. BTH inhibited the release of some of the key psoriatic cytokines such as tumor necrosis factor alpha, IL-8, IL-6, and CCL27 through the downregulation of NF-kappa B in normal human keratinocytes. Moreover, it impaired signal transducers and activators of transcription 3 (STAT3) phosphorylation and translocation to the nucleus, which resulted in decreased keratinocyte proliferation. These results were confirmed in vivo in two murine models of psoriasis: the epidermal hyperplasia induced by 12-O-tetradecanoylphorbol-13-acetate and the imiquimod-induced skin inflammation model. In both cases, topical administration of BTH prevented skin infiltration and hyperplasia through suppression of NF-kappa B and STAT3 phosphorylation. Our results confirm the pivotal role of both transcriptional factors in skin inflammation, as occurs in psoriasis, and highlight the potential of small molecules as therapeutic agents for the treatment of this skin disease, with BTH being a potential candidate for future drug research.