Cutting edge: dexamethasone negatively regulates Syk in mast cells by up-regulating SRC-like adaptor protein.
We have identified Src-like adaptor protein (SLAP) as one of several dexamethasone-inducible inhibitory regulators in mast cells. SLAP is a known inhibitor of T cell signaling and interacts with the tyrosine kinase, Zap70. Exposure of RBL-2H3 mast cells to dexamethasone markedly increased expression of SLAP. Cells so exposed or made to overexpress SLAP exhibited reduced Ag-stimulated phosphorylation of Syk (a cognate of Zap70), linker for activation of T cells, phospholipase Cgamma, and ERK. Ca(2+) mobilization, Ca(2+)-dependent degranulation, and ERK-dependent release of arachidonic acid were suppressed as well. Small interfering RNA directed against SLAP blocked the induction of SLAP and reversed the inhibitory effects of dexamethasone on phosphorylation of Syk, linker for activation of T cells, and phospholipase Cgamma, but not downstream events, which are likely suppressed by up-regulation of downstream of tyrosine kinase-1 and MAPK phosphatase-1. The induction of these inhibitory regulators may contribute to the immunosuppressive activity of dexamethasone in mast cells.
Hiragun
Takaaki
T
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Peng
Ze
Z
Beaven
Michael A
MA
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000096:biosynthesis*; D051381:Rats; D000072377:Syk Kinase; D015854:Up-Regulation / Q000187:drug effects*
D048868:Adaptor Proteins, Signal Transducing; D000893:Anti-Inflammatory Agents; D047908:Intracellular Signaling Peptides and Proteins; C490636:Sla protein, rat; D003907:Dexamethasone; D011505:Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D000072377:Syk Kinase; C000606898:Syk protein, rat