Salt-inducible kinases are required for the IL-33-dependent secretion of cytokines and chemokines in mast cells.
Salt-inducible kinases are required for the IL-33-dependent secretion of cytokines and chemokines in mast cells.
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DOI：
10.1016/j.jbc.2021.100428
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Cohen P
中科院分区：
文献类型：
--
作者：
Darling NJ;Arthur JSC;Cohen P
细胞因子和趋化因子是气道高反应性、免疫细胞浸润和炎症的重要调节因子，并且当肥大细胞被白细胞介素-33（IL-33）刺激时产生。在这里，我们建立了盐诱导激酶（SIKs）所需的IL-33刺激的IL-13，GM-CSF和TNF的转录，因此这些细胞因子的生产。IL-33刺激的IL-13、粒细胞-巨噬细胞集落刺激因子和肿瘤坏死因子的分泌在来自表达激酶失活的SIK 3突变体的小鼠的胎肝来源的肥大细胞中强烈减少，并且在表达激酶失活的SIK 2和SIK 3突变体的细胞中被废除。这些细胞因子和几种趋化因子的IL-33依赖性分泌在SIK 2/3双敲除的骨髓源性肥大细胞（BMMC）中也被消除，在SIK 3 KO细胞中减少，但在表达SIK 1和SIK 2的激酶失活突变体或缺乏SIK 2表达的BMMC中几乎没有影响。在SIK 2基因敲除的BMMC中，SIK 3的表达显著增加。我们的研究确定了SIK 2和SIK 3在产生触发气道炎症的炎症介质中的重要作用。SIKs的作用不依赖于IκB激酶β、IκB激酶β介导的NF-κ B依赖性基因转录以及丝裂原活化蛋白激酶家族成员p38α和c-jun N-末端激酶的激活。我们的研究结果表明，SIK 2和SIK 3的双重抑制剂可能具有治疗肥大细胞驱动的疾病的治疗潜力。
Cytokines and chemokines are important regulators of airway hyper-responsiveness, immune cell infiltration, and inflammation and are produced when mast cells are stimulated with interleukin-33 (IL-33). Here, we establish that the salt-inducible kinases (SIKs) are required for the IL-33-stimulated transcription of il13, gm-csf and tnf and hence the production of these cytokines. The IL-33–stimulated secretion of IL-13, granulocyte-macrophage colony stimulating factor, and tumor necrosis factor was strongly reduced in fetal liver–derived mast cells from mice expressing a kinase-inactive mutant of SIK3 and abolished in cells expressing kinase-inactive mutants of SIK2 and SIK3. The IL-33–dependent secretion of these cytokines and several chemokines was also abolished in SIK2/3 double knock-out bone marrow–derived mast cells (BMMC), reduced in SIK3 KO cells but little affected in BMMC expressing kinase-inactive mutants of SIK1 and SIK2 or lacking SIK2 expression. In SIK2 knock-out BMMC, the expression of SIK3 was greatly increased. Our studies identify essential roles for SIK2 and SIK3 in producing inflammatory mediators that trigger airway inflammation. The effects of SIKs were independent of IκB kinase β, IκB kinase β-mediated NF-κB-dependent gene transcription, and activation of the mitogen-activated protein kinase family members p38α and c-jun N-terminal kinases. Our results suggest that dual inhibitors of SIK2 and SIK3 may have therapeutic potential for the treatment of mast cell–driven diseases.
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DOI：
10.1165/ajrcmb.10.5.8179909
发表时间：
1994-05-01
影响因子：
6.4
作者：
BRADDING, P;ROBERTS, JA;HOLGATE, ST
通讯作者：
HOLGATE, ST
DOI：
10.1016/j.trsl.2015.08.004
发表时间：
2016-01
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
--
作者：
Durham AL;Caramori G;Chung KF;Adcock IM
通讯作者：
Adcock IM
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
影响因子：
1.9
作者：
Hamzaoui, Agnes;Berraies, Anissa;Kamel, Hamzaoui
通讯作者：
Kamel, Hamzaoui
影响因子：
14.2
作者：
Junttila, Ilkka S.;Watson, Cynthia;Kummola, Laura;Chen, Xi;Hu-Li, Jane;Guo, Liying;Yagi, Ryoji;Paul, William E.
通讯作者：
Paul, William E.