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The JAK1/JAK2‐ inhibitor ruxolitinib inhibits mast cell degranulation and cytokine release
Author(s) -
Hermans Maud A. W.,
Schrijver Benjamin,
van HoltenNeelen Conny C.P.A.,
Gerth van Wijk Roy,
van Hagen P. Martin,
van Daele Paul L.A.,
Dik Willem A.
Publication year - 2018
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/cea.13217
Subject(s) - ruxolitinib , degranulation , mast cell , histamine , pharmacology , cytokine , stat5 , chemistry , cancer research , signal transduction , medicine , immunology , receptor , biochemistry , bone marrow , myelofibrosis
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 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.