Corticosteroid inhibition of growth-related oncogene protein-α 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, Fan Chung Kian

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Expression of the inflammatory chemokine, growth-related oncogene protein-α (GRO-α), from airway smooth muscle cells (ASMC) is regulated by pathways involving NF-κB and MAPK activation. We determined the effects of dexamethasone on GRO-α induced by IL-1β or TNF-α with respect to the role of MAPK pathways and of MAPK phosphatase-1 (MKP-1). Human ASMC were studied in primary culture at coniuence. Dexamethasone (10 -8-10-5 M) partially inhibited GRO-α expression and release induced by IL-1β and TNF-α; this was associated with an inhibition of JNK, but not of p38 or ERK phosphorylation. Together with IL-1β or TNF-α, 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-1β- and dexamethasone-induced MKP-1 by 50%, JNK phosphorylation was doubled. The inhibitory effect of dexamethasone on GRO-α 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-1β-induced release of GRO-α, but the inhibitory effects of dexamethasone were preserved. Nuclear translocation of the glucocorticoid receptor was increased in ASMC exposed to dexamethasone and IL-1β. Using chromatin immunoprecipitation assay, glucocorticoid receptor binding to the MKP-1 promoter was increased by IL-1β and dexamethasone compared with either alone. Glucocorticoids and IL-1β or TNF-α modulate GRO-α release partly through the inhibition of JNK pathway, resulting from an up-regulation of MKP-1 expression.

Original languageEnglish
Pages (from-to)7366-7375
Number of pages10
JournalJournal of Immunology
Volume178
Issue number11
Publication statusPublished - Jun 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Immunology

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