Inhibition of thymic stromal lymphopoietin production by FK3453.
Inhibition of thymic stromal lymphopoietin production by FK3453.
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FK3453 抑制胸腺基质淋巴细胞生成素的产生。
DOI：
10.1016/j.jphs.2022.05.005
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Hirasawa N.
中科院分区：
文献类型：
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作者：
Segawa R;Ishihara R;Hiratsuka M;Hirasawa N.
为了防止过敏性疾病的发生和加重，有必要调节过度的Th 2型免疫应答。胸腺基质淋巴细胞生成素（thymic stromal lymphopoietin，TSLP）在Th 1/Th 2平衡向Th 2优势转变中起重要作用，是一个可治疗的靶点。在这项研究中，使用药物重新定位策略，我们确定了6-（2-氨基-4-苯基嘧啶-5-基）-2-异丙基哒嗪-3（2 H）-酮（FK 3453）作为一种新的TSLP产生抑制剂。FK 3453抑制KCMH-1小鼠角质形成细胞系中TSLP的组成性产生，并抑制PAM 212细胞中12-O-十四酰佛波醇-13-乙酸酯（TPA）诱导的TSLP的组成性产生。FK 3453还抑制由肿瘤坏死因子α（TNF-α）、白细胞介素（IL）-4、成纤维细胞刺激脂肽-1、蛋白酶激活受体激动剂和TPA混合物诱导的正常人表皮角质形成细胞（NHEK）中TSLP mRNA的表达。尽管FK 3453除了抑制TSLP外，还抑制TPA诱导的NHEK中IL-33表达，但不抑制TNF-α和IL-6的产生。此外，FK 3453不抑制MAP激酶（ERK）磷酸化。我们已经证实，在脂多糖诱导的气囊型炎症模型中，FK 3453局部给药可抑制TSLP的产生。FK 3453可能是预防过敏性疾病发作和加重的新型药物的先导化合物。
To prevent the onset and aggravation of allergic diseases, it is necessary to modulate excessive Th2-type immune responses. It is well accepted that thymic stromal lymphopoietin (TSLP) plays important roles in the change of Th1/Th2 balance to Th2 dominance and would be a druggable target. In this study, using a drug repositioning strategy, we identified 6-(2-amino-4-phenylpyrimidine-5-yl)-2-isopropylpyridazin-3(2H)-one (FK3453) as a novel inhibitor of TSLP production. FK3453 inhibited constitutive production of TSLP in the KCMH-1 mouse keratinocyte cell line and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced one in PAM212 cells. FK3453 also inhibitedTSLPmRNA expression induced by a mixture of tumor necrosis factor alpha (TNF-α), interleukin (IL)-4, fibroblast-stimulation lipopeptide-1, and protease activated-receptor agonist and TPA in normal human epidermal keratinocytes (NHEKs). Although FK3453 inhibited TPA-induced IL-33 expression in NHEKs in addition to TSLP, it did not inhibit TNF-α and IL-6 production. In addition, FK3453 did not inhibit MAP kinase (ERK) phosphorylation. We have confirmed that topical treatment with FK3453 inhibited TSLP production in the lipopolysaccharide-induced air pouch-type inflammation model. FK3453 could be a lead compound for a novel type of medicine which prevents the onset and aggravation of allergic diseases.