A chalcone derivative suppresses TSLP induction in mice and human keratinocytes through binding to BET family proteins
A chalcone derivative suppresses TSLP induction in mice and human keratinocytes through binding to BET family proteins
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查尔酮衍生物通过与 BET 家族蛋白结合抑制小鼠和人类角质形成细胞中 TSLP 的诱导
DOI：
10.1016/j.bcp.2021.114819
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发表时间：
2021
影响因子：
5.8
通讯作者：
Hirasawa Noriyasu
中科院分区：
文献类型：
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作者：
Segawa Ryosuke;Takeda Hiroyuki;Yokoyama Takeshi;Ishida Momoha;Miyata Chihiro;Saito Taiji;Ishihara Ryosuke;Nakagita Tomoya;Sasano Yusuke;Kanoh Naoki;Iwabuchi Yoshiharu;Mizuguchi Mineyuki;Hiratsuka Masahiro;Hirasawa Noriyasu
虽然过敏性疾病的治疗已经有所改善，但副作用和治疗抗性仍然是挑战。迫切需要用于过敏性疾病的新的治疗药物。胸腺基质淋巴细胞生成素（TSLP）是防治过敏性疾病的细胞因子靶点。由于TSLP在过敏性疾病中由上皮细胞产生，TSLP抑制剂可能成为新的抗过敏药物。我们先前鉴定了一种新的TSLP产生抑制剂，命名为16 D10。然而，其行动目标仍然不明确。在这项研究中，我们通过基于AlphaScreen的高通量筛选从24，000个人类蛋白质阵列中发现了与16 D10结合的蛋白质，并确定了溴结构域和额外末端（BET）家族蛋白作为靶标。我们还澄清了16 D10和BET家族蛋白质之间的相互作用的详细模式，使用X射线晶体学。此外，我们证实BET家族蛋白的抑制剂抑制小鼠和人角质形成细胞系中的TSLP诱导以及IL-33和IL-36γ表达。综上所述，我们的研究结果表明，BET家族蛋白参与了16 D10对TSLP产生的抑制。这些蛋白质可以通过角质形成细胞中的TSLP调节而促进特应性皮炎的病理学，并且具有作为过敏性疾病的治疗靶点的潜力。
Although treatments for allergic diseases have improved, side effects and treatment resistance remain as challenges. New therapeutic drugs for allergic diseases are urgently required. Thymic stromal lymphopoietin (TSLP) is a cytokine target for prevention and treatment of allergic diseases. Since TSLP is produced from epithelial cells in allergic diseases, TSLP inhibitors may be new anti-allergic drugs. We previously identified a new inhibitor of TSLP production, named 16D10. However, its target of action remained unclarified. In this study, we found proteins binding to 16D10 from 24,000 human protein arrays by AlphaScreen-based high-throughput screening and identified bromodomain and extra-terminal (BET) family proteins as targets. We also clarified the detailed mode of interaction between 16D10 and a BET family protein using X-ray crystallography. Furthermore, we confirmed that inhibitors of BET family proteins suppressed TSLP induction and IL-33 and IL-36γ expression in both mouse and human keratinocyte cell lines. Taken together, our findings suggest that BET family proteins are involved in the suppression of TSLP production by 16D10. These proteins can contribute to the pathology of atopic dermatitis via TSLP regulation in keratinocytes and have potential as therapeutic targets in allergic diseases.