Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità (ISS), Rome, Italy.
Front Immunol. 2024 Aug 12;15:1443704. doi: 10.3389/fimmu.2024.1443704. eCollection 2024.
The Janus kinase (JAK) family includes four cytoplasmic tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) constitutively bound to several cytokine receptors. JAKs phosphorylate downstream signal transducers and activators of transcription (STAT). JAK-STAT5 pathways play a critical role in basophil and mast cell activation. Previous studies have demonstrated that inhibitors of JAK-STAT pathway blocked the activation of mast cells and basophils.
In this study, we investigated the effects of ruxolitinib, a JAK1/2 inhibitor, on IgE- and IL-3-mediated release of mediators from human basophils, as well as substance P-induced mediator release from skin mast cells (HSMCs).
Ruxolitinib concentration-dependently inhibited IgE-mediated release of preformed (histamine) and synthesized mediators (leukotriene C) from human basophils. Ruxolitinib also inhibited anti-IgE- and IL-3-mediated cytokine (IL-4 and IL-13) release from basophils, as well as the secretion of preformed mediators (histamine, tryptase, and chymase) from substance P-activated HSMCs.
These results indicate that ruxolitinib, inhibiting the release of several mediators from human basophils and mast cells, is a potential candidate for the treatment of inflammatory disorders.
Janus 激酶（JAK）家族包括四个细胞质酪氨酸激酶（JAK1、JAK2、JAK3 和 TYK2），它们与几种细胞因子受体持续结合。JAKs 磷酸化下游信号转导子和转录激活子（STAT）。JAK-STAT5 途径在嗜碱性粒细胞和肥大细胞激活中起着关键作用。先前的研究表明，JAK-STAT 途径抑制剂可阻断肥大细胞和嗜碱性粒细胞的激活。
在这项研究中，我们研究了 JAK1/2 抑制剂鲁索替尼对 IgE 和 IL-3 介导的人嗜碱性粒细胞介质释放以及 P 物质诱导的皮肤肥大细胞（HSMCs）介质释放的影响。
鲁索替尼浓度依赖性地抑制 IgE 介导的人嗜碱性粒细胞预先形成的（组胺）和合成介质（白细胞三烯 C）的释放。鲁索替尼还抑制抗 IgE 和 IL-3 介导的细胞因子（IL-4 和 IL-13）从嗜碱性粒细胞释放，以及 P 物质激活的 HSMCs 中预先形成的介质（组胺、胰蛋白酶和糜蛋白酶）的分泌。
这些结果表明，鲁索替尼抑制几种人嗜碱性粒细胞和肥大细胞介质的释放，是治疗炎症性疾病的潜在候选药物。
