We have previously shown that Janus kinase 3, a member of the family of non-receptor protein tyrosine kinases, plays a critical role in the regulation of Fc epsilon RI-mediated mast cell responses. In the current study, we investigated the role of another JAK family member, JAK2, in these responses. Our results show that the treatment of IgE-sensitized mouse mast cells with an inhibitor of JAk2 (AG490) blocked the release of leukotriene C-4 in a dose-dependent fashion after antigen challenge. However, prostaglandin PG D-2 Production and degranulation were not affected under identical experimental conditions. Transfection of RBL-2H3 mast cells with JAK-2 specific small interfering RNA resulted in a 50% reduction of LTC4 release in response to Fc epsilon RI crosslinking, but did not inhibit mast cell degranulation or calcium ionophore-induced LTC4 release, indicating involvement of JAK2 in IgE receptor-mediated leukotriene release. Taken together, these data suggest that JAK2 is a critical regulator of IgE/antigen-induced production of LTC4 in mast cells. (C) 2009 Elsevier Inc. All rights reserved.