JAK1/JAK2抑制剂鲁索利替尼可抑制肥大细胞脱颗粒和细胞因子释放
2018/12/24
摘要
背景：肥大细胞增多症以异常肥大细胞（mast cells, MC）累积为特征。肥大细胞增多症患者由于MC介质水平增加而呈现出多种症状。 因此抑制MC介质的释放将会明显受益。 然而，迄今为止，很少有现成药物可以有效降低MC介质水平。 在MC激活中有janus 激酶2（janus kinase 2，JAK2）与信号转导和激活转录5（STAT5）信号通路参与的证据正在缓慢积累。 干扰JAK2-STAT5途径可能抑制MC介质释放。 鲁索利替尼是一种JAK1 / JAK2抑制剂，明确可以减轻骨髓增生性肿瘤患者的瘙痒和疲劳等症状。然而，尚缺乏关于鲁索利替尼如何影响人类肥大细胞活性的进一步研究。
目的：研究鲁索利替尼对人肥大细胞系LAD2和HMC1的JAK1 / 2抑制作用。
方法：用P物质，可待因或钙离子载体A23817刺激LAD2和HMC1。探索鲁索利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）以及对IL-6，IL-13，MCP-1和TNF-α产生的影响。使用选择性STAT5抑制剂匹莫齐特探索STAT5的活化。
结果：鲁索利替尼以浓度依赖方式有效抑制可待因和物质P诱导的脱颗粒。 鲁索利替尼还显著抑制由A23817和物质P诱导的IL-6，TNF-α和MCP-1的产生。选择性STAT5抑制剂匹莫齐特可减少脱颗粒，并抑制由A23817和物质P诱导的细胞因子产生。
结论和临床相关性：本研究表明JAK1 / JAK2抑制剂鲁索利替尼可能通过阻止STAT5激活，从而抑制MC活性。 这使得JAK-STAT途径成为有效治疗靶标，以减轻如肥大细胞增多症以及许多其他MC介质相关疾病的症状负担。
The JAK1/JAK2- inhibitor ruxolitinib inhibits mast cell degranulation and cytokine release.
Hermans MAW, Schrijver B, van Holten-Neelen CCPA, Gerth van Wijk R, van Hagen PM, van Daele PLA, Dik WA.
Clin Exp Allergy. 2018; 48(11):1412-1420
Abstract
BACKGROUND: 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.
OBJECTIVE: To investigate the effect of JAK1/2-inhibition with ruxolitinib in the human mast cell lines LAD2 and HMC1.
METHODS: 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.
RESULTS: 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 MC activity, 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.
背景：肥大细胞增多症以异常肥大细胞（mast cells, MC）累积为特征。肥大细胞增多症患者由于MC介质水平增加而呈现出多种症状。 因此抑制MC介质的释放将会明显受益。 然而，迄今为止，很少有现成药物可以有效降低MC介质水平。 在MC激活中有janus 激酶2（janus kinase 2，JAK2）与信号转导和激活转录5（STAT5）信号通路参与的证据正在缓慢积累。 干扰JAK2-STAT5途径可能抑制MC介质释放。 鲁索利替尼是一种JAK1 / JAK2抑制剂，明确可以减轻骨髓增生性肿瘤患者的瘙痒和疲劳等症状。然而，尚缺乏关于鲁索利替尼如何影响人类肥大细胞活性的进一步研究。
目的：研究鲁索利替尼对人肥大细胞系LAD2和HMC1的JAK1 / 2抑制作用。
方法：用P物质，可待因或钙离子载体A23817刺激LAD2和HMC1。探索鲁索利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）以及对IL-6，IL-13，MCP-1和TNF-α产生的影响。使用选择性STAT5抑制剂匹莫齐特探索STAT5的活化。
结果：鲁索利替尼以浓度依赖方式有效抑制可待因和物质P诱导的脱颗粒。 鲁索利替尼还显著抑制由A23817和物质P诱导的IL-6，TNF-α和MCP-1的产生。选择性STAT5抑制剂匹莫齐特可减少脱颗粒，并抑制由A23817和物质P诱导的细胞因子产生。
结论和临床相关性：本研究表明JAK1 / JAK2抑制剂鲁索利替尼可能通过阻止STAT5激活，从而抑制MC活性。 这使得JAK-STAT途径成为有效治疗靶标，以减轻如肥大细胞增多症以及许多其他MC介质相关疾病的症状负担。
(王刚1张红萍1 四川大学华西医院中西医结合科呼吸病组 610041 摘译)
（Clin Exp Allergy. 2018; 48(11):1412-1420.）
（Clin Exp Allergy. 2018; 48(11):1412-1420.）
The JAK1/JAK2- inhibitor ruxolitinib inhibits mast cell degranulation and cytokine release.
Hermans MAW, Schrijver B, van Holten-Neelen CCPA, Gerth van Wijk R, van Hagen PM, van Daele PLA, Dik WA.
Clin Exp Allergy. 2018; 48(11):1412-1420
Abstract
BACKGROUND: 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.
OBJECTIVE: To investigate the effect of JAK1/2-inhibition with ruxolitinib in the human mast cell lines LAD2 and HMC1.
METHODS: 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.
RESULTS: 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 MC activity, 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.
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