Targeting Janus Kinase 3 in Mast Cells Prevents Immediate Hypersensitivity Reactions and Anaphylaxis

Ravi Malaviya,Demin Zhu,Ilker Dibirdik,Fatih M Uckun

doi:10.1074/jbc.274.38.27028

Abstract

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.

Highlights

Acute allergic reactions, known as immediate hypersensitivity reactions, including anaphylaxis with a potentially fatal outcome, are triggered by three major classes of proinflammatory mediators, namely preformed granule-associated bioactive amines and acid hydrolases (e.g. ␤-hexosaminidase), newly synthesized arachidonic acid metabolites (e.g. leukotriene (LT)1 C4, prostaglandin D2, and platelet activating factor), and a number of proinflammatory vasoactive cytokines (e.g. tumor necrosis factor (TNF) ␣ and interleukin (IL)-6) [1, 2]
We found that the IgE/antigen-induced degranulation and mediator release are substantially reduced with Jak3Ϫ/Ϫ mast cells from JAK3-null mice that were generated by targeted disruption of Jak3 gene in embryonic stem cells [17], indicating that JAK3 plays a pivotal role in IgE receptor/Fc⑀RI-mediated mast cell responses both in vitro and in vivo
Expression and IgE Receptor/Fc⑀RI-mediated Activation of Janus Kinase 3 in Mast Cells—As shown in Fig. 1A, JAK3 is abundantly expressed in RBL-2H3 mast cells

Summary

Introduction

Known as immediate (type I) hypersensitivity reactions, including anaphylaxis with a potentially fatal outcome, are triggered by three major classes of proinflammatory mediators, namely preformed granule-associated bioactive amines (e.g. histamine and serotonin) and acid hydrolases (e.g. ␤-hexosaminidase), newly synthesized arachidonic acid metabolites (e.g. leukotriene (LT)1 C4, prostaglandin D2, and platelet activating factor), and a number of proinflammatory vasoactive cytokines (e.g. tumor necrosis factor (TNF) ␣ and interleukin (IL)-6) [1, 2]. Cross-linking of the IgE receptors on RBL-2H3 mast cells that were previously sensitized by a monoclonal anti-DNP-IgE antibody with the specific antigen DNP-BSA resulted in enhanced tyrosine phosphorylation of JAK3 regardless of its base-line phosphorylation state

Results

Conclusion