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J Biol Chem, Vol. 274, Issue 38, 27028-27038, September 17, 1999
§,
From the Departments of 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/Fc Allergy,
§ Immunology, ¶ Biochemistry, and Drug Discovery
Program, Hughes Institute, St. Paul, Minnesota 55113
RI 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/FcRI 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/FcRI-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.
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