P38 Mitogen-activated protein kinase–induced glucocorticoid receptor phosphorylation reduces its activity: Role in steroid-insensitive asthma Elvis Irusen,

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Presentation transcript:

p38 Mitogen-activated protein kinase–induced glucocorticoid receptor phosphorylation reduces its activity: Role in steroid-insensitive asthma Elvis Irusen, MD*, John G. Matthews, MB BS*, Atsushi Takahashi, MD, Peter J. Barnes, ScD, Kian F. Chung, DSc, Ian M. Adcock, PhD Journal of Allergy and Clinical Immunology Volume 109, Issue 4, Pages 649-657 (April 2002) DOI: 10.1067/mai.2002.122465 Copyright © 2002 Mosby, Inc. Terms and Conditions

Fig. 1 GR binding parameters of PBMCs isolated from healthy subjects and patients with severe asthma and the effects of prednisolone. Ligand-binding affinity (Kd) in cytosolic and nuclear compartments (A) was measured in 6 healthy subjects, 19 oral steroid–dependent (SD) asthmatic patients, and 9 asthmatic patients whose symptoms were controlled with ICSs (ICS) . The receptor number in cytosolic and nuclear compartments was also measured in these subjects (B) . Data are expressed as means ± SEM (**P < .01, ***P < .001). The effect of prednisolone (40 mg/d for 7 days) on percent predicted FEV1(C) , GR affinity (D) , and receptor number (E) in steroid-dependent and ICS subjects is also shown. Data are expressed as individual data points (*P < .05). Journal of Allergy and Clinical Immunology 2002 109, 649-657DOI: (10.1067/mai.2002.122465) Copyright © 2002 Mosby, Inc. Terms and Conditions

Fig. 2 IL-2/IL-4–induced attenuated ligand-binding affinity is mediated by p38 MAPK. A , IL-2 and IL-4 (both at 50 IU/mL) reduce ligand-binding affinity (Kd) in healthy subjects after 48 hours. This effect is not seen with medium alone and is blocked by the p38 MAPK inhibitor SB203580 (1 μmol/L). B , Western blot analysis showing that IL-2/IL-4 treatment (both at 50 IU/mL) stimulates phosphorylation of ATF-2 (P-ATF-2) at 1 and 24 hours. This effect is inhibited by SB203580 (1 μmol/L). Equal loading was confirmed by measuring the expression of nonphosphorylated ATF-2 in the same samples. Results are representative of 3 separate experiments. Densitometric analysis of the data is shown in the panel below. C , Effect of 48 hours' incubation with medium alone, IL-2/IL-4 (both at 50 ng/mL), IL-2/IL-4 and SB203580 (SB ; 1 μmol/L), wortmannin (Wort ; 5 nmol/L), IL-10 (3 ng/mL), Ro318220 (Ro ; 10 nmol/L), or PD098059 (PD ; 10 μmol/L) on GR ligand-binding affinity (Kd). D , GR receptor numbers of PBMCs isolated from steroid-dependent subjects. Results are expressed as means ± SEM for 8 steroid-dependent patients and compared with values obtained at baseline (*P < .05, **P < .01). Journal of Allergy and Clinical Immunology 2002 109, 649-657DOI: (10.1067/mai.2002.122465) Copyright © 2002 Mosby, Inc. Terms and Conditions

Fig. 3 IL-2/IL-4 induces p38-mediated GR phosphorylation. PBMCs isolated from healthy subjects were treated with IL-2/IL-4 (both 50 IU/mL) for 48 hours in the presence of 32P-labeled orthophosphate. GR was immunoprecipitated with a GRα/β antibody and fractionated with SDS-PAGE. A , Autoradiograph of gel showing induction of 32P incorporation into GR by means of IL-2/IL-4 treatment was inhibited by SB203580 (1 μmol/L). B , upper panel , Western blot analysis of immunoprecipitated GR showing no induction of GR expression after incubation of cells with IL-2/IL-4 or with SB203580. Lower panel , No expression of GRβ was detected with a GRβ-specific commercially available antibody (Affinity Bioreagents). Results are representative of 3 independent experiments. Positive controls from HeLa cell extracts for GRα and GRβ are also shown. The lower intense bands are due to detection of the 50-kd IgG heavy chain and are used as loading controls. C , Western blot analysis of IL-2/IL-4–induced serine phosphorylation of immunoprecipitated GRα/β obtained from CD2+ T cells. The effect is inhibited by means of cotreatment with SB203580 (1 μmol/L). Journal of Allergy and Clinical Immunology 2002 109, 649-657DOI: (10.1067/mai.2002.122465) Copyright © 2002 Mosby, Inc. Terms and Conditions

Fig. 4 Effect of IL-2 and IL-4 treatment on cytokine release. A , Effect of dexamethasone on GM-CSF production in LPS-stimulated (10 ng/mL) cultures of PBMCs from normal subjects pretreated with IL-2 and IL-4 (50 IU/mL). ***P < .001 compared with medium alone. ##P < .01 compared with stimualted cells. #P < .05 compared with stimuated cells. B , Effect of dexamethasone on GM-CSF production in PMA/PHA-stimulated cultures of PBMCs from normal subjects pretreated with IL-2 and IL-4 (both at 50IU/mL). **P < .01. *P < .05. NS, Not significant. C , Effect of IL-2 and IL-4 cotreatment on dexamethasone inhibition of LPS-induced IL-10 release in PBMCs from normal subjects. *P < .05. Results are expressed as means ± SEMs of at least 5 independent experiments. Journal of Allergy and Clinical Immunology 2002 109, 649-657DOI: (10.1067/mai.2002.122465) Copyright © 2002 Mosby, Inc. Terms and Conditions