IL-12-induced T-bet expression and IFN γ release in lymphocytes from asthmatics—Role of MAPkinases ERK-1/-2, p38MAPK and effect of dexamethasone

• Published in: Respiratory medicine Vol. 101; no. 6; pp. 1321 - 1330
• Main Authors: Koch, Andrea, Raidl, Maria, Lux, Michael, Müller, Katja, Büning, Hildegard, Humme, Sibille, Erdmann, Erland
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 01-06-2007
• Subjects: Biological and medical sciences; Chronic obstructive pulmonary disease, asthma; Medical sciences; Pneumology; Pulmonary/Respiratory; Dexamethasone; IL; broncho-alveolar lavage; T-box expressed in T-cells; mRNA; Extracellular signal-regulated protein kinases ERK-1; AHR; T-bet; BAL; reverse transcripted polymerase chain reaction; ERK-1; Human peripheral blood T-lymphocytes; ERK-2; 2; DEX; extracellular signal-regulated protein-kinase-1; RT-PCR; elongation factor 1-alpha; airway hyper-responsiveness; EF-1 α; messenger ribonucleic acid; Interferon (IFN) γ; interleukin; Human; Lung disease; Extracellular signal-regulated protein kinase; Respiratory disease; Enzyme; Cytokine; Mitogen-activated protein kinase; Interleukin 12; Interferon (IFN)γ; Gene expression; Blood; Asthma; Extracellular signal- regulated protein kinases ERK-1; Immunological investigation; T-Lymphocyte; Bronchus disease; Obstructive pulmonary disease; Release; Gamma interferon; Pneumology
• ISSN: 0954-6111; 1532-3064
• DOI: 10.1016/j.rmed.2006.10.010

Summary The transcription factor T-box-expressed-in-T-cells (T-bet) is required for TH 1 lymphocyte differentiation, regulates the IL-12-induced expression of the TH 1-specific cytokine IFN γ 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 IFN γ expression was assessed in peripheral blood lymphocytes of 10 atopic asthmatics and 10 nonatopic normals. IFN γ 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 IFN γ 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 IFN γ release by ∼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 IFN γ expression independently of T-bet and this regulatory role of ERK-1/-2 on IFN γ release is impaired in asthma. The therapeutic benefit of dexamethasone on T-bet and IFN γ production seems to be critical.