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via Mitogen-Activated Kinase Phosphatase-1 in Airway Smooth Muscle Cells1Experimental Medicine, Airway Studies Section, National Heart and Lung Institute, Imperial College, London, United Kingdom
Expression of the inflammatory chemokine, growth-related oncogene protein-
(GRO-), from airway smooth muscle cells (ASMC) is regulated by pathways involving NF-
B and MAPK activation. We determined the effects of dexamethasone on GRO- induced by IL-1
or TNF- with respect to the role of MAPK pathways and of MAPK phosphatase-1 (MKP-1). Human ASMC were studied in primary culture at confluence. Dexamethasone (10–8–10–5 M) partially inhibited GRO- expression and release induced by IL-1 and TNF-; this was associated with an inhibition of JNK, but not of p38 or ERK phosphorylation. Together with IL-1 or TNF-, dexamethasone rapidly induced mRNA and protein expression of MKP-1, which dephosphorylates MAPKs. Using MKP-1 small interfering RNA (siRNA) to block the expression of IL-1- and dexamethasone-induced MKP-1 by 50%, JNK phosphorylation was doubled. The inhibitory effect of dexamethasone on GRO- release was partially reversed in ASMC treated with MKP-1 siRNA compared with those treated with scrambled siRNA. In contrast, overexpression of MKP-1 led to a reduction in IL-1-induced release of GRO-, but the inhibitory effects of dexamethasone were preserved. Nuclear translocation of the glucocorticoid receptor was increased in ASMC exposed to dexamethasone and IL-1. Using chromatin immunoprecipitation assay, glucocorticoid receptor binding to the MKP-1 promoter was increased by IL-1 and dexamethasone compared with either alone. Glucocorticoids and IL-1 or TNF- modulate GRO- release partly through the inhibition of JNK pathway, resulting from an up-regulation of MKP-1 expression.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Wellcome Trust.
2 Address correspondence and reprint requests to Dr. Kian Fan Chung, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, U.K. E-mail address: f.chung{at}imperial.ac.uk
3 Abbreviations used in this paper: ASMC, airway smooth muscle cell; ChIP, chromatin immunoprecipitation; GR, glucocorticoid receptor; GRO-, growth-related oncogene protein-; MKP, MAPK phosphatase; SFM, serum-free medium; siRNA, small interfering RNA; TSA, trichostatin A.
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