Corticosteroid inhibition of growth-related oncogene protein-alpha via mitogen-activated kinase phosphatase-1 in airway smooth muscle cells

• Published in: Journal of Immunology Vol. 178; no. 11; pp. 7366 - 7375
• Main Authors: Issa, Razao, Xie, Shaoping, Khorasani, Nadia, Sukkar, Maria, Adcock, Ian M, Lee, Kang-Yun, Chung, Kian Fan
• Format: Journal Article
• Language: English
• Published: United States 01.06.2007
• Subjects: Active Transport, Cell Nucleus - drug effects; Bronchi - cytology; Bronchi - drug effects; Bronchi - enzymology; Bronchi - metabolism; Cell Cycle Proteins - biosynthesis; Cell Cycle Proteins - physiology; Cells, Cultured; Chemokine CXCL1; Chemokines, CXC - antagonists & inhibitors; Chemokines, CXC - biosynthesis; Chemokines, CXC - genetics; Chemokines, CXC - metabolism; Dexamethasone - antagonists & inhibitors; Dexamethasone - pharmacology; DNA - metabolism; Dual Specificity Phosphatase 1; Humans; Immediate-Early Proteins - biosynthesis; Immediate-Early Proteins - physiology; Interleukin-1beta - physiology; Muscle, Smooth - cytology; Muscle, Smooth - drug effects; Muscle, Smooth - enzymology; Muscle, Smooth - metabolism; NF-kappa B - metabolism; Phosphoprotein Phosphatases - biosynthesis; Phosphoprotein Phosphatases - physiology; Protein Binding - drug effects; Protein Phosphatase 1; Protein Tyrosine Phosphatases - biosynthesis; Protein Tyrosine Phosphatases - physiology; Receptors, Glucocorticoid - metabolism; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; RNA, Small Interfering - genetics; RNA, Small Interfering - pharmacology; Transfection; Up-Regulation - drug effects
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.178.11.7366

Expression of the inflammatory chemokine, growth-related oncogene protein-alpha (GRO-alpha), from airway smooth muscle cells (ASMC) is regulated by pathways involving NF-kappaB and MAPK activation. We determined the effects of dexamethasone on GRO-alpha induced by IL-1beta or TNF-alpha 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-alpha expression and release induced by IL-1beta and TNF-alpha; this was associated with an inhibition of JNK, but not of p38 or ERK phosphorylation. Together with IL-1beta or TNF-alpha, 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-1beta- and dexamethasone-induced MKP-1 by 50%, JNK phosphorylation was doubled. The inhibitory effect of dexamethasone on GRO-alpha 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-1beta-induced release of GRO-alpha, but the inhibitory effects of dexamethasone were preserved. Nuclear translocation of the glucocorticoid receptor was increased in ASMC exposed to dexamethasone and IL-1beta. Using chromatin immunoprecipitation assay, glucocorticoid receptor binding to the MKP-1 promoter was increased by IL-1beta and dexamethasone compared with either alone. Glucocorticoids and IL-1beta or TNF-alpha modulate GRO-alpha release partly through the inhibition of JNK pathway, resulting from an up-regulation of MKP-1 expression.