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

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 confluence. 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.

Inhibition of NF-κB-dependent Transcription by MKP-1

“…This has led to considerable interest in developing ligands of GR that show reduced transactivation yet maintain transrepression activity (51). However, a complete loss of GR transactivation would impair the ability to induce MKP-1, and this would impact not only on the repression of NF-B (current study) but also on AP-1 (52) and on the expression of various inflammatory genes, including cyclooxygenase-2, GRO␣ (growth-regulated oncogene ␣), and IL-6 (31,32,53). Somewhat paradoxically, most screens for transrepression make use of standard reporter gene assays for NF-B, AP-1, or parts of the promoter regions of relevant inflammatory genes, such as E-selectin (7).…”

Dexamethasone potentiates the antiangiogenic activity of docetaxel in castration-resistant prostate cancer

“…Indeed, DEX has been shown to induce resistance to several cytotoxic agents, including the taxane, paclitaxel, in cells isolated from surgical resections of prostate tumours (Zhang et al, 2006) and to a range of cytotoxics in xenograft models of CaP (Zhang et al, 2007). Studies in macrophages, endothelial, airway smooth muscle and cancer cells have shown that DEX-induced glucocorticoid receptor signalling increases the expression of MAPK phosphatase-1, resulting in decreased MAPK signalling in these cells and contributing to the anti-inflammatory effect (Wu et al, 2005;Abraham et al, 2006;Furst et al, 2007;Issa et al, 2007). Interestingly, overexpression of MAPK phosphatase-1 has been shown to attenuate taxaneinduced, proapoptotic JNK signalling in breast cancer cells (Wu et al, 2005).…”

Selective Prostacyclin Receptor Agonism Augments Glucocorticoid-Induced Gene Expression in Human Bronchial Epithelial Cells

“…kip2 (22,(37)(38)(39)(40), and were selected to examine the interaction between dexamethasone and taprostene (or forskolin).…”

“…This gene encodes an enzyme that dephosphorylates (inactivates) the three core mammalian MAPKs (p38 MAPK, ERK, and JNK) that are central to the induction of many proinflammatory genes (e.g., growth-related oncogene-␣) (Ref. 40). As shown in Figs.…”