Genetic and biochemical evidence for a critical role of Janus kinase (JAK)-3 in mast cell-mediated type I hypersensitivity reactions.
We investigated the role of JAK3 in IgE receptor/FcepsilonRI-mediated mast cell responses. IgE/antigen induced degranulation and mediator release were substantially reduced with Jak3-/- mast cells from JAK3-null mice that were generated by targeted disruption of Jak3 gene in embryonic stem cells. Further, treatment of mast cells with 3'bromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P154), a potent inhibitor of JAK3, inhibited degranulation and proinflammatory mediator release after IgE receptor/ FcepsilonRI crosslinking. Thus, JAK3 plays a pivotal role in IgE receptor/ FcepsilonRI-mediated mast cell responses and targeting JAK3 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, USA.
Uckun
F M
FM
D000818:Animals; D001854:Bone Marrow Cells; D015550:Cell Degranulation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004140:Dinitrophenols / Q000276:immunology; D017353:Gene Deletion; D006632:Histamine / Q000378:metabolism; D006967:Hypersensitivity / Q000201:enzymology / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy; D007073:Immunoglobulin E / Q000276:immunology / Q000378:metabolism; D053616:Janus Kinase 3; D017997:Leukotriene C4 / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology; D011940:Receptor Aggregation; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism; D019089:Stem Cell Factor / Q000494:pharmacology
D004140:Dinitrophenols; D011799:Quinazolines; D017455:Receptors, IgE; D019089:Stem Cell Factor; C113888:WHI P154; D017997:Leukotriene C4; D007073:Immunoglobulin E; D006632:Histamine; D011505:Protein-Tyrosine Kinases; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3