Corticosteroid inhibition of growth-related oncogene protein-alpha via mitogen-activated kinase phosphatase-1 in airway smooth muscle cells.
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.
Issa
Razao
R
Experimental Medicine, Airway Studies Section, National Heart and Lung Institute, Imperial College, London, United Kingdom.
Xie
Shaoping
S
Khorasani
Nadia
N
Sukkar
Maria
M
Adcock
Ian M
IM
Lee
Kang-Yun
KY
Chung
Kian Fan
KF
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000502:physiology*; D002478:Cells, Cultured; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D054638:Dual Specificity Phosphatase 1; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000502:physiology*; D053583:Interleukin-1beta / Q000502:physiology; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis / Q000502:physiology*; D011485:Protein Binding / Q000187:drug effects; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
C475829:CXCL1 protein, human; D018797:Cell Cycle Proteins; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D017874:Immediate-Early Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D004247:DNA; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases