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! Fc epsilon RI-mediated ma st cell responses. IgE/antigen induced degranulation and mediator release w ere substantially reduced with Jak3(-/-) mast cells from JAK3-null mice tha t were generated by targeted disruption of Jak3 gene in embryonic stem cell s. Further, treatment of mast cells with 3'bromo-4'-hydroxylphenyl)amino-6, 7-dimethoxyquinazoline (WHI-P154), a potent inhibitor of JAK3, inhibited de granulation and proinflammatory mediator release after IgE receptor! Fc eps ilon RI crosslinking. Thus, JAK3 plays a pivotal role in IgE receptor! Fc e psilon RI-mediated mast cell responses and targeting JAK3 may provide the b asis for new and effective treatment as well as prevention programs for mas t cell-mediated allergic reactions. (C) 1999 Academic Press.