Inhibition by dexamethasone of antigen-induced c-Jun N-terminal kinase activation in rat basophilic leukemia cells.
Antigen stimulation of IgE-sensitized rat basophilic leukemia RBL-2H3 cells induced activation of c-Jun N-terminal kinase (JNK) within a few minutes with maximum activity attained 40 min later. The increase in JNK activity was accompanied with an increase in phosphorylation of c-Jun in the cells. The Ag-induced JNK activation was inhibited by the phosphatidylinositol 3-kinase inhibitors wortmannin (10-100 nM) and LY 294002 (100 microM) but not by the protein kinase C inhibitors calphostin C (1 and 3 microM) and Ro 31-8425 (1 and 3 microM). Pretreatment with dexamethasone (10 and 100 nM) for 18 h inhibited the Ag-induced increase in JNK activity in a concentration-dependent manner. At least 6 h of preincubation with dexamethasone was necessary to inhibit the Ag-induced JNK activation. The phosphorylation of c-Jun induced by the Ag stimulation was reduced by pretreatment with dexamethasone without reduction of the content of c-Jun protein. The Ag-induced activation of the JNK kinase kinase mitogen-activated protein kinase-extracellular signal-regulated kinase kinase-1 was also inhibited by pretreatment with dexamethasone at 10 and 100 nM. These findings indicate that dexamethasone reduces JNK protein level and inhibits the Ag-induced activation of JNK resulting in the inhibition of c-Jun phosphorylation.
Hirasawa
N
N
Department of Pathophysiological Biochemistry, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. hirasawa@mail.pharm.tohoku.ac.jp
Sato
Y
Y
Fujita
Y
Y
Mue
S
S
Ohuchi
K
K
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D002867:Chromones / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D004140:Dinitrophenols / Q000276:immunology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007073:Immunoglobulin E / Q000276:immunology*; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D015471:Leukemia, Basophilic, Acute / Q000473:pathology*; D048728:MAP Kinase Kinase Kinase 1; D008301:Maleimides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D012709:Serum Albumin / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D002867:Chromones; D004140:Dinitrophenols; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D009025:Morpholines; D009281:Naphthalenes; D009363:Neoplasm Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D012709:Serum Albumin; D018808:Transcription Factor AP-1; C058064:dinitrophenyl-human serum albumin conjugate; C071924:Ro 31-8425; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007073:Immunoglobulin E; D003907:Dexamethasone; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; C058819:calphostin C; D000077191:Wortmannin