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

• Published in: The Journal of biological chemistry 1999-09, Vol.274 (38), p.27028-27038
• Main Authors: Malaviya, Ravi, Zhu, DeMin, Dibirdik, Ilker, Uckun, Fatih M.
• Format: Article
• Language: English
• Subjects: AFc receptors; Anaphylaxis - enzymology; Animals; Calcium - metabolism; Cell Line; Electrophoresis, Polyacrylamide Gel; Enzyme Inhibitors - pharmacology; Humans; Hypersensitivity, Immediate - enzymology; Janus Kinase 3; Male; Mast Cells - enzymology; Mice; Mice, Inbred BALB C; Protein-Tyrosine Kinases - metabolism; Quinazolines - pharmacology; Receptors, IgE - metabolism
• ISSN: 0021-9258; 1083-351X
• 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/FcεRI 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/FcεRI 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/FcεRI-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.