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

J Immunol. 2007 Jun 1;178(11):7366-75. doi: 10.4049/jimmunol.178.11.7366.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • DNA / metabolism
  • Dexamethasone / antagonists & inhibitors
  • Dexamethasone / pharmacology*
  • 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*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology
  • Receptors, Glucocorticoid / metabolism
  • Transfection
  • Up-Regulation / drug effects

Substances

  • CXCL1 protein, human
  • Cell Cycle Proteins
  • Chemokine CXCL1
  • Chemokines, CXC
  • Immediate-Early Proteins
  • Interleukin-1beta
  • NF-kappa B
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Glucocorticoid
  • Dexamethasone
  • DNA
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 1
  • DUSP1 protein, human
  • Dual Specificity Phosphatase 1
  • Protein Tyrosine Phosphatases