Department of Internal Medicine, Sections of Allergy and Clinical Immunology, Erasmus MC, Rotterdam, The Netherlands.
Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
Clin Exp Allergy. 2018 Nov;48(11):1412-1420. doi: 10.1111/cea.13217. Epub 2018 Aug 3.
Mastocytosis is characterized by the accumulation of aberrant mast cells (MC). Patients suffering from mastocytosis suffer from a wide range of symptoms due to increased levels of MC mediators. It would therefore be of great benefit to inhibit MC mediator release. However, to date there are few drugs available that are known to effectively lower MC mediator levels. The evidence for the involvement of the janus kinase 2 (JAK2)-signal transducer and activation of transcription 5 (STAT5) signalling pathway in MC activation is slowly accumulating. Interference with the JAK2-STAT5 pathway might inhibit MC mediator release. Ruxolitinib, a JAK1/JAK2 inhibitor, indeed decreases symptoms like pruritus and fatigue in patients with myeloproliferative neoplasms. Yet, detailed studies on how ruxolitinib affects human mast cell activity are lacking.
To investigate the effect of JAK1/2-inhibition with ruxolitinib in the human mast cell lines LAD2 and HMC1.
LAD2 and HMC1 were stimulated with substance P, codeine or the calcium ionophore A23817. The effect of ruxolitinib on mast cell degranulation (via measurement of β-hexosaminidase, histamine release and CD63 membrane expression) and IL-6, IL-13, MCP-1 and TNF-α production was investigated. The involvement of STAT5 activation was explored using the selective STAT5 inhibitor pimozide.
Ruxolitinib effectively inhibited codeine- and substance P-induced degranulation in a concentration-dependent manner. Ruxolitinib also significantly inhibited the production of IL-6, TNF-α and MCP-1 as induced by A23817 and substance P. Selective STAT5 inhibition with pimozide resulted in diminished degranulation and inhibition of cytokine production as induced by A23817 and substance P.
CONCLUSIONS & CLINICAL RELEVANCE: This study demonstrates that the JAK1/JAK2 inhibitor ruxolitinib can inhibit MCactivity, possibly through prevention of STAT5 activation. This renders the JAK-STAT pathway as an interesting target for therapy to release symptom burden in mastocytosis and many other MC mediator-related diseases.
肥大细胞增多症的特征是异常肥大细胞（MC）的积累。由于 MC 介质水平升高，患有肥大细胞增多症的患者会出现多种症状。因此，抑制 MC 介质释放将大有裨益。然而，迄今为止，可用的药物很少，已知这些药物能有效降低 MC 介质水平。Janus 激酶 2（JAK2）-信号转导和转录激活因子 5（STAT5）信号通路在 MC 激活中的作用的证据正在缓慢积累。干扰 JAK2-STAT5 途径可能会抑制 MC 介质的释放。JAK1/JAK2 抑制剂鲁索替尼确实可以减轻骨髓增生性肿瘤患者的瘙痒和疲劳等症状。然而，缺乏关于鲁索替尼如何影响人肥大细胞活性的详细研究。
研究 JAK1/2 抑制剂鲁索替尼对人肥大细胞系 LAD2 和 HMC1 的影响。
用 P 物质、可待因或钙离子载体 A23817 刺激 LAD2 和 HMC1。研究了鲁索替尼对肥大细胞脱颗粒（通过测量β-己糖胺酶、组胺释放和 CD63 膜表达）和白细胞介素-6（IL-6）、白细胞介素-13（IL-13）、单核细胞趋化蛋白-1（MCP-1）和肿瘤坏死因子-α（TNF-α）产生的影响。使用选择性 STAT5 抑制剂吡莫唑来探索 STAT5 激活的参与。
鲁索替尼可有效抑制浓度依赖性的可待因和 P 物质诱导的脱颗粒。鲁索替尼还显著抑制 A23817 和 P 物质诱导的 IL-6、TNF-α 和 MCP-1 的产生。用吡莫唑选择性抑制 STAT5 可导致 A23817 和 P 物质诱导的脱颗粒和细胞因子产生减少。
这项研究表明，JAK1/JAK2 抑制剂鲁索替尼可以抑制 MC 活性，可能通过阻止 STAT5 激活。这使得 JAK-STAT 途径成为治疗肥大细胞增多症和许多其他与 MC 介质相关疾病以减轻症状负担的一个有趣靶点。
