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.
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.
Koch
Andrea
A
Department of Pneumology, University of Cologne, Medical Clinic III, Joseph-Stelzmann-Strasse 9, 50924 Köln (Cologne), Germany. andrea.koch@uni-koeln.de
Raidl
Maria
M
Lux
Michael
M
Müller
Katja
K
Büning
Hildegard
H
Humme
Sibille
S
Erdmann
Erland
E
D000328:Adult; D001249:Asthma / Q000276:immunology*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000097:blood*; D018664:Interleukin-12 / Q000276:immunology*; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D000098815:T-bet Transcription Factor
D004791:Enzyme Inhibitors; D005419:Flavonoids; D005938:Glucocorticoids; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D003907:Dexamethasone; D007371:Interferon-gamma; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one