Malaviya R, Zhu D, Dibirdik I, Uckun F M
Department of Allergy, Hughes Institute, St. Paul, Minnesota 55113, USA.
J Biol Chem. 1999 Sep 17;274(38):27028-38. doi: 10.1074/jbc.274.38.27028.
Janus kinase 3 (JAK3), a member of the Janus family protein-tyrosine kinases, is expressed in mast cells, and its enzymatic activity is enhanced by IgE receptor/FcepsilonRI cross-linking. Selective inhibition of JAK3 in mast cells with 4-(4'-hydroxylphenyl)-amino-6, 7-dimethoxyquinazoline) (WHI-P131) blocked the phospholipase C activation, calcium mobilization, and activation of microtubule-associated protein kinase after lgE receptor/FcepsilonRI cross-linking. Treatment of IgE-sensitized rodent as well as human mast cells with WHI-P131 effectively inhibited the activation-associated morphological changes, degranulation, and proinflammatory mediator release after specific antigen challenge without affecting the functional integrity of the distal secretory machinery. In vivo administration of the JAK3 inhibitor WHI-P131 prevented mast cell degranulation and development of cutaneous as well as systemic fatal anaphylaxis in mice at nontoxic dose levels. Thus, JAK3 plays a pivotal role in IgE receptor/FcepsilonRI-mediated mast cell responses, and targeting JAK3 with a specific inhibitor, such as WHI-P131, may provide the basis for new and effective treatment as well as prevention programs for mast cell-mediated allergic reactions.
Janus激酶3（JAK3）是Janus家族蛋白酪氨酸激酶的成员之一，在肥大细胞中表达，其酶活性通过IgE受体/FcepsilonRI交联而增强。用4-（4'-羟基苯基）-氨基-6,7-二甲氧基喹唑啉（WHI-P131）选择性抑制肥大细胞中的JAK3，可阻断IgE受体/FcepsilonRI交联后的磷脂酶C激活、钙动员和微管相关蛋白激酶激活。用WHI-P131处理IgE致敏的啮齿动物和人肥大细胞，可有效抑制特异性抗原攻击后与激活相关的形态变化、脱颗粒和促炎介质释放，而不影响远端分泌机制的功能完整性。在无毒剂量水平下，体内给予JAK3抑制剂WHI-P131可预防小鼠肥大细胞脱颗粒以及皮肤和全身性致命过敏反应的发生。因此，JAK3在IgE受体/FcepsilonRI介导的肥大细胞反应中起关键作用，用特异性抑制剂（如WHI-P131）靶向JAK3可能为肥大细胞介导的过敏反应的新的有效治疗和预防方案提供基础。
