TWEAK/Fn14 Activation Contributes to the Pathogenesis of Bullous Pemphigoid
TWEAK/Fn14 Activation Contributes to the Pathogenesis of Bullous Pemphigoid
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TWEAK/Fn14 激活有助于大疱性类天疱疮的发病机制
DOI：
10.1016/j.jid.2017.03.019
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发表时间：
2017-07-01
影响因子：
6.5
通讯作者：
Xia, Yumin
中科院分区：
文献类型：
--
作者：
Liu, Yale;Peng, Lingling;Xia, Yumin
TWEAK通过其Fn 14受体参与各种细胞效应。可溶性TWEAK水平升高与红斑狼疮、类风湿性关节炎或皮肌炎患者的系统性自身免疫相关。然而，TWEAK在大疱性类天疱疮（BP）中的作用仍然未知。在这项研究中，我们发现血清TWEAK水平升高，血清TWEAK和抗BP 180抗体之间呈正相关。免疫组化显示TWEAK和Fn 14的强表达，并暗示TWEAK和BP 180的表达在BP患者的皮肤样本中的相反关系。体外TWEAK刺激降低HaCaT细胞中BP 180的表达，并抑制细胞与培养皿的粘附。因此，Fn 14小干扰RNA的转染保留了BP 180并保护细胞免于失去粘附。此外，TWEAK的这种作用与细胞外信号调节激酶和NF-κ B途径以及下游亚当斯的激活有关。通过用小干扰RNA沉默ADAM 17，我们发现ADAM 17参与了TWEAK诱导的BP 180丢失。因此，TWEAK可能通过减少BP 180表达和细胞粘附，涉及ERK和NF-κ B通路的激活，从而促进BP的发病。TWEAK可作为BP的生物标志物或治疗靶点。
TWEAK participates in various cellular effects by engaging its receptor of Fn14. Increased levels of soluble TWEAK are associated with systemic autoimmunity in patients with lupus erythematosus, rheumatoid arthritis, or dermatomyositis. However, the role of TWEAK in bullous pemphigoid (BP) remains unknown. In this study, we found an elevated serum level of TWEAK and a positive correlation between serum TWEAK and anti-BP180 antibodies. Immunohistochemistry showed strong TWEAK and Fn14 expression and implied an opposite relationship between the TWEAK and BP180 expression in skin samples from BP patients. In vitro TWEAK stimuli reduced BP180 expression in HaCaT cells and inhibited the adhesion of cells to the culture dish. Consistently, the transfection of Fn14 small interfering RNA preserved BP180 and protected cells from losing adherence. Moreover, such effect of TWEAK correlated with activation of the extracellular signal-regulated kinase and NF KB pathways and downstream ADAMs. By silencing ADAM17 with small interfering RNA, we showed that ADAM17 participated in TWEAK-induced BP180 loss. Therefore, TWEAK may contribute to the pathogenesis of BP by reducing BP180 expression and cellular adherence, involving the activation of ERK and NF-KB pathways. TWEAK may serve as a biomarker or therapeutic target of BP.