Targeting Janus kinase 3 in mast cells prevents immediate hypersensitivity reactions and anaphylaxis.
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.
Malaviya
R
R
Department of Allergy, Hughes Institute, St. Paul, Minnesota 55113, USA.
Zhu
D
D
Dibirdik
I
I
Uckun
F M
FM
D000707:Anaphylaxis / Q000201:enzymology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000201:enzymology*; D053616:Janus Kinase 3; D008297:Male; D008407:Mast Cells / Q000201:enzymology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D017455:Receptors, IgE / Q000378:metabolism
D004791:Enzyme Inhibitors; D011799:Quinazolines; D017455:Receptors, IgE; C116180:WHI P131; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3; D002118:Calcium