Activation of the mitogen-activated protein kinase cascade is suppressed by low concentrations of dexamethasone in mast cells.
Antigen stimulation of mast cells via the IgE receptor, Fc epsilon RI, results in recruitment of the cytosolic tyrosine kinases, Lyn and Syk, and the phosphorylation of proteins. We examined the effects of the glucocorticoid dexamethasone on these events in a cultured (RBL-2H3) mast cell line. Nanomolar concentrations of dexamethasone suppressed phosphorylation of proteins that were associated with the activation of the mitogen-activated protein (MAP) kinase/phospholipase A2 pathway without inhibiting initial events. For example, tyrosine phosphorylation of the subunits of Fc epsilon RI, Lyn, or Syk or of the Ras-guanine nucleotide exchange factor, Vav, was not suppressed in cells treated with up to 1 microM dexamethasone. In contrast, phosphorylation of Raf1, MEK1, p42mapk, and cytosolic phospholipase A2, as well as the associated increase in MAP kinase activity and release of arachidonic acid, were markedly inhibited in cells treated with as little as 10 nM dexamethasone--a concentration that only partially inhibited hydrolysis of inositol phospholipids or release of secretory granules. Prolonged exposure to dexamethasone also resulted in a partial decrease in expression of MEK1, p42mapk, and cytosolic phospholipase A2, which may contribute further to the effects of dexamethasone on this pathway. Activation of the MAP kinase/phospholipase A2 pathway by the calcium-mobilizing agent thapsigargin was similarly suppressed in dexamethasone-treated cells. These findings suggested that an early step in the pathway, possibly a step immediately before the activation of Raf1, was suppressed by low concentrations of dexamethasone.
Rider
L G
LG
Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA.
Hirasawa
N
N
Santini
F
F
Beaven
M A
MA
D000818:Animals; D000941:Antigens / Q000502:physiology; D001095:Arachidonic Acids / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D004306:Dose-Response Relationship, Immunologic; D004789:Enzyme Activation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015471:Leukemia, Basophilic, Acute; D048369:MAP Kinase Kinase 1; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology* / Q000276:immunology; D019950:Mitogen-Activated Protein Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D010741:Phospholipases A / Q000187:drug effects / Q000378:metabolism; D054467:Phospholipases A2; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D051381:Rats; D017455:Receptors, IgE / Q000187:drug effects / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000187:drug effects / Q000378:metabolism; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
D000941:Antigens; D001095:Arachidonic Acids; D007166:Immunosuppressive Agents; D011518:Proto-Oncogene Proteins; D017455:Receptors, IgE; D014443:Tyrosine; D019284:Thapsigargin; D003907:Dexamethasone; D011505:Protein-Tyrosine Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D010741:Phospholipases A; D054467:Phospholipases A2