1. IL-12-induced T-bet expression and IFNgamma release in lymphocytes from asthmatics--role of MAPkinases ERK-1/-2, p38(MAPK) and effect of dexamethasone.
- Author
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Koch A, Raidl M, Lux M, Müller K, Büning H, Humme S, and Erdmann E
- Subjects
- Adult, Cells, Cultured, Dexamethasone pharmacology, Enzyme Inhibitors pharmacology, Enzyme-Linked Immunosorbent Assay methods, Female, Flavonoids pharmacology, Gene Expression Regulation drug effects, Gene Expression Regulation immunology, Glucocorticoids pharmacology, Humans, Imidazoles pharmacology, Male, Mitogen-Activated Protein Kinase 3 antagonists & inhibitors, Mitogen-Activated Protein Kinase 3 physiology, Pyridines pharmacology, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction methods, T-Box Domain Proteins biosynthesis, T-Box Domain Proteins genetics, T-Lymphocytes immunology, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors, p38 Mitogen-Activated Protein Kinases physiology, T-bet Transcription Factor, Asthma immunology, Interferon-gamma blood, Interleukin-12 immunology, Mitogen-Activated Protein Kinases physiology, T-Box Domain Proteins blood
- Abstract
The transcription factor T-box-expressed-in-T-cells (T-bet) is required for T(H)1 lymphocyte differentiation, regulates the IL-12-induced expression of the T(H)1-specific cytokine IFNgamma and may be dysregulated in asthmatics. The modulatory role of extracellular signal-regulated kinase (ERK)-1/-2, p38mitogen-activated protein kinase (MAPK) and dexamethasone on IL-12 induced T-bet and IFNgamma expression was assessed in peripheral blood lymphocytes of 10 atopic asthmatics and 10 nonatopic normals. IFNgamma production was dependent on phosphorylation of ERK-1/-2 and p38MAPK, as examined by PD098059, an inhibitor of the upstream activator of MAPKkinase (MKK-1), and SB203580, an inhibitor of p38MAPK. The inhibitory effect of PD098059 on IFNgamma release was decreased in asthmatic T-cells compared with normals. The IL-12-induced T-bet expression and the inhibitory effect of SB203580 were increased in asthmatic T-cells compared with normals. Dexamethasone blocked the IL-12-induced T-bet expression in asthmatic T-cells completely and decreased IL-12-induced IFNgamma release by approximately 50%, which occurred to the same extent in asthmatic and normal T-cells. In conclusion, (1) p38MAPK-pathway rather than ERK-pathway may play a more basic role in the regulation of the increased T-bet expression in asthma, and (2) ERK- and p38MAPK-activation modulate IFNgamma expression independently of T-bet and this regulatory role of ERK-1/-2 on IFNgamma release is impaired in asthma. The therapeutic benefit of dexamethasone on T-bet and IFNgamma production seems to be critical.
- Published
- 2007
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