![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
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 up-regulated 4-fold in dexamethasone-treated RBL-2H3 cells. The up-regulation was apparent with as little as 1 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 the expression of small interfering RNA directed against Dok-1, which enhanced activation of MAP kinase and subsequent release of arachidonic acid and tumor necrosis factor-
. These findings identify Dok-1 as mediator of the antiallergic actions of dexamethasone and as a negative regulator of the MAP kinase pathway and downstream release of inflammatory mediators.
Address correspondence to: Dr. Michael A. Beaven, Building 10/Room 8N109, National Institutes of Health, Bethesda, MD 20892-1760. E-mail: beavenm{at}mail.nih.gov
This article has been cited by other articles:
|
|
 |
|
  R. Newton and N. S. Holden Separating Transrepression and Transactivation: A Distressing Divorce for the Glucocorticoid Receptor? Mol. Pharmacol., October 1, 2007; 72(4): 799 - 809. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Scheving, R. Buchanan, M. A. Krause, X. Zhang, M. C. Stevenson, and W. E. Russell Dexamethasone modulates ErbB tyrosine kinase expression and signaling through multiple and redundant mechanisms in cultured rat hepatocytes Am J Physiol Gastrointest Liver Physiol, September 1, 2007; 293(3): G552 - G559. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Peng, T. Hiragun, H. Qiao, and M. A Beaven Glucocorticoids Suppress Activation of Mast Cells through induction of Inhibitory Regulators of Signaling Pathways J. Immunol., April 1, 2007; 178(MeetingAbstracts): S173 - S173.
|
|
|
|
|
|
T. Hiragun, Z. Peng, and M. A. Beaven Cutting Edge: Dexamethasone Negatively Regulates Syk in Mast Cells by Up-Regulating Src-Like Adaptor Protein J. Immunol., August 15, 2006; 177(4): 2047 - 2050. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Damazo, S. Yona, R. J. Flower, M. Perretti, and S. M. Oliani Spatial and Temporal Profiles for Anti-Inflammatory Gene Expression in Leukocytes during a Resolving Model of Peritonitis J. Immunol., April 1, 2006; 176(7): 4410 - 4418. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
