Resatorvid-based Pharmacological Antagonism of Cutaneous TLR4 Blocks UV-induced NF-B and AP-1 Signaling in Keratinocytes and Mouse Skin
Resatorvid-based Pharmacological Antagonism of Cutaneous TLR4 Blocks UV-induced NF-B and AP-1 Signaling in Keratinocytes and Mouse Skin
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DOI：
10.1111/php.12659
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发表时间：
2016-11-01
影响因子：
3.3
通讯作者：
Dickinson, Sally E.
中科院分区：
文献类型：
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作者：
Janda, Jaroslav;Burkett, Nichole B.;Dickinson, Sally E.
皮肤暴露于太阳紫外线(UV)辐射是皮肤癌的主要致癌因素，迫切需要改进的分子策略来有效地化学预防非黑色素瘤皮肤癌(NMSC)。Toll样受体4(TLR4)信号已被证明可推动皮肤炎症、光免疫抑制和化学致癌。在这里，我们研究了针对皮肤TLR4的遗传和药物拮抗的可行性，以抑制紫外线诱导的角质形成细胞和小鼠皮肤中的NF-B和AP-1信号。利用人类皮肤的免疫组织化学和蛋白质组微阵列分析，我们首次证明在角质形成细胞从正常皮肤到光化性角化病的过程中，TLR4的表达显著增加，在进一步发展到鳞癌的过程中也可以检测到TLR4的表达。接下来，我们证明了基于siRNA的TLR4基因抑制阻断了培养的角质形成细胞中紫外线诱导的应激信号。重要的是，我们观察到一种分子靶向的临床TLR4拮抗剂resatorvid(TAK-242)可以阻断紫外线诱导的角质形成细胞和局部处理的小鼠皮肤中的NF-B和MAP-1活性以及细胞因子(IL-6、IL-8和IL-10)的表达。综上所述，我们的数据显示，药理学上的TLR4拮抗剂可以抑制紫外线诱导的皮肤信号，未来的实验将探索TLR4指导的策略预防NMSC的潜力。
Cutaneous exposure to solar ultraviolet (UV) radiation is a major causative factor in skin carcinogenesis, and improved molecular strategies for efficacious chemoprevention of nonmelanoma skin cancer (NMSC) are urgently needed. Toll-like receptor 4 (TLR4) signaling has been shown to drive skin inflammation, photoimmunosuppression, and chemical carcinogenesis. Here we have examined the feasibility of genetic and pharmacological antagonism targeting cutaneous TLR4 for the suppression of UV-induced NF-B and AP-1 signaling in keratinocytes and mouse skin. Using immunohistochemical and proteomic microarray analysis of human skin, we demonstrate for the first time that a significant increase in expression of TLR4 occurs in keratinocytes during the progression from normal skin to actinic keratosis, also detectible during further progression to squamous cell carcinoma. Next, we demonstrate that siRNA-based genetic TLR4 inhibition blocks UV-induced stress signaling in cultured keratinocytes. Importantly, we observed that resatorvid (TAK-242), a molecularly targeted clinical TLR4 antagonist, blocks UV-induced NF-B and MAP kinase/AP-1 activity and cytokine expression (Il-6, Il-8, and Il-10) in cultured keratinocytes and in topically treated murine skin. Taken together, our data reveal that pharmacological TLR4 antagonism can suppress UV-induced cutaneous signaling, and future experiments will explore the potential of TLR4-directed strategies for prevention of NMSC.