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Received for publication October 22, 2004.
Revised December 16, 2004.
Accepted for publication December 17, 2004.
The glucocorticoid, dexamethasone, suppresses antigen-induced degranulation, cytokine production, and intermediate signaling events in RBL-2H3 mast cells, although the exact mechanisms are uncertain. By microarray analysis, we discovered that expression of the inhibitory adaptor protein, downstream of tyrosine kinase (Dok)-1, was upregulated fourfold in dexamethasone-treated RBL-2H3 cells. The upregulation was apparent with as little as 1 nM to 10 nM dexamethasone. Treatment with dexamethasone also enhanced tyrosine phosphorylation of Dok-1, augmented recruitment of Ras GTPase-activating protein (RasGAP) by Dok-1, and inhibited activation of the mitogen-activated protein (MAP) kinase pathway in antigen-stimulated cells. The same effects were obtained by transient overexpression of Dok-1 but not by overexpression of Dok-1 that was mutated in RasGAP-binding domain. The negative regulatory role of Dok-1 was further validated by expression of small interfering RNA directed against Dok-1 which enhanced activation of MAP kinase and subsequent release of arachidonic acid and TNF
. These findings identify Dok-1 as mediator of the anti-allergic actions of dexamethasone and as a negative regulator of the MAP kinase pathway and downstream release of inflammatory mediators.
Key words:
Prostanoid, Tumor necrosis factor, Glucorticoids/Mineralocorticoids, Ras, Raf family, MAP Kinase, Leukocytes/Mast cells
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