Reversal of corticosteroid insensitivity by p38 MAPK inhibition in peripheral blood mononuclear cells from COPD
Author(s)
Khorasani, N
Baker, J
Johnson, M
Chung, KF
Bhavsar, PK
Type
Journal Article
Abstract
Background: Corticosteroids (CS) have limited efficacy in the treatment of chronic obstructive
pulmonary disease (COPD). p38 mitogen-activated protein kinase (MAPK) activation is
increased in lung macrophages of COPD. We investigated whether p38 MAPK inhibition
can modulate CS insensitivity of peripheral blood mononuclear cells (PBMCs) from patients
with COPD.
Methods: PBMCs from patients with COPD (n=8) or healthy smokers (n=8) were exposed to
lipopolysaccharide (LPS) with a selective p38 MAPK inhibitor (GW856553; 10-10–10-6
M),
with dexamethasone (10-10–10-6
M), or with both. Phosphorylated glucocorticoid receptor (GR)
was measured by Western blot.
Results: Baseline (P,0.01) and LPS-induced (P,0.05) CXCL8 release was greater in PBMCs
from COPD compared to healthy smokers. Inhibition of LPS-induced CXCL8 release by dexamethasone
(10-6
M) was reduced, and baseline and LPS-induced p38 MAPK activation increased
in PBMCs of COPD. GW856553 (10-9
and 10-10 M) synergistically increased the inhibitory
effect of dexamethasone (10-8
and 10-6
M) on LPS-induced CXCL8 release in COPD. Similar
results were obtained for IL-6 release. GW856553 inhibited dexamethasone- and LPS-activated
phosphorylation of serine 211 on GR. CS insensitivity in COPD PBMCs is reversed by inhibition
of p38 MAPK activity, partly by preventing phosphorylation of GR at serine 211.
Conclusion: p38 MAPK inhibition may be beneficial in COPD by restoring CS sensitivity.
pulmonary disease (COPD). p38 mitogen-activated protein kinase (MAPK) activation is
increased in lung macrophages of COPD. We investigated whether p38 MAPK inhibition
can modulate CS insensitivity of peripheral blood mononuclear cells (PBMCs) from patients
with COPD.
Methods: PBMCs from patients with COPD (n=8) or healthy smokers (n=8) were exposed to
lipopolysaccharide (LPS) with a selective p38 MAPK inhibitor (GW856553; 10-10–10-6
M),
with dexamethasone (10-10–10-6
M), or with both. Phosphorylated glucocorticoid receptor (GR)
was measured by Western blot.
Results: Baseline (P,0.01) and LPS-induced (P,0.05) CXCL8 release was greater in PBMCs
from COPD compared to healthy smokers. Inhibition of LPS-induced CXCL8 release by dexamethasone
(10-6
M) was reduced, and baseline and LPS-induced p38 MAPK activation increased
in PBMCs of COPD. GW856553 (10-9
and 10-10 M) synergistically increased the inhibitory
effect of dexamethasone (10-8
and 10-6
M) on LPS-induced CXCL8 release in COPD. Similar
results were obtained for IL-6 release. GW856553 inhibited dexamethasone- and LPS-activated
phosphorylation of serine 211 on GR. CS insensitivity in COPD PBMCs is reversed by inhibition
of p38 MAPK activity, partly by preventing phosphorylation of GR at serine 211.
Conclusion: p38 MAPK inhibition may be beneficial in COPD by restoring CS sensitivity.
Date Issued
2015-02-04
Date Acceptance
2014-10-10
Citation
International Journal of Chronic Obstructive Pulmonary Disease, 2015, 10 (1), pp.283-291
ISSN
1176-9106
Publisher
Dove Medical Press
Start Page
283
End Page
291
Journal / Book Title
International Journal of Chronic Obstructive Pulmonary Disease
Volume
10
Issue
1
Copyright Statement
© 2015 Khorasani et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0)
License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further
permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on
how to request permission may be found at: http://www.dovepress.com/permissions.php
License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further
permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on
how to request permission may be found at: http://www.dovepress.com/permissions.php
License URL
Subjects
Science & Technology
Life Sciences & Biomedicine
Respiratory System
glucocorticoid receptor
p38 mitogen-activated protein kinase
GLUCOCORTICOID-RECEPTOR PHOSPHORYLATION
OBSTRUCTIVE PULMONARY-DISEASE
MESSENGER-RNA STABILITY
PROTEIN-KINASE MAPK
GENE-EXPRESSION
ALVEOLAR MACROPHAGES
SIGNALING PATHWAYS
CYTOKINE RELEASE
TOBACCO-SMOKE
EXACERBATIONS
Publication Status
Published