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Corticosteroid Inhibition of Growth-Related Oncogene Protein-Alpha via Mitogen-Activated Kinase phosphatase-1 in Airway Smooth Muscle Cells

Corticosteroid Inhibition of Growth-Related Oncogene Protein-Alpha via Mitogen-Activated Kinase phosphatase-1 in Airway Smooth Muscle Cells

Razao Issa, Shaoping Xie, Nadia Khorasani, Maria Sukkar, Ian M Adcock, Kang-Yun Lee, Kian Fan Chung

J Immunol. 2007 Jun 1;178(11):7366-75.

PMID: 17513787

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42415796	Protein Phosphatase Inhibitor 1 human			Price

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