A Dissociated Glucocorticoid Receptor Modulator Reduces Airway Hyperresponsiveness and Inflammation in a Mouse Model of Asthma

Abstract

The glucocorticoid receptor (GR) is a transcription factor able to support either target gene activation via direct binding to DNA or gene repression via interfering with the activity of various proinflammatory transcription factors. An improved therapeutic profile for combating chronic inflammatory diseases has been reported through selectively modulating the GR by only triggering its transrepression function. We have studied in this paper the activity of Compound A (CpdA), a dissociated GR modulator favoring GR monomer formation, in a predominantly Th2-driven asthma model. CpdA acted similarly to the glucocorticoid dexamethasone (DEX) in counteracting OVA-induced airway hyperresponsiveness, recruitment of eosinophils, dendritic cells, neutrophils, B and T cells, and macrophages in bronchoalveolar lavage fluid, lung Th2, Tc2, Th17, Tc17, and mast cell infiltration, collagen deposition, and goblet cell metaplasia. Both CpdA and DEX inhibited Th2 cytokine production in bronchoalveolar lavage as well as nuclear translocation of NF-κB and its subsequent recruitment onto the IκBα promoter in the lung. By contrast, DEX but not CpdA induces expression of the GR-dependent model gene MAPK phosphatase 1 in the lung, confirming the dissociative action of CpdA. Mechanistically, we demonstrate that CpdA inhibited IL-4–induced STAT6 translocation and that GR is essential for CpdA to mediate chemokine repression. In conclusion, we clearly show in this study the anti-inflammatory effect of CpdA in a Th2-driven asthma model in the absence of transactivation, suggesting a potential therapeutic benefit of this strategy.

Effect of the Plant Derivative Compound A on the Production of Corticosteroid-Resistant Chemokines in Airway Smooth Muscle Cells

“…These marked differences in CpdA inhibitory profile point to two important conclusions: (1) it suggests that different mechanisms regulate the expression of GC-insensitive chemokines, and (2) it suggests that CpdA inhibits the expression of these GC-resistant chemokines by acting on various pathways. Our observation is in agreement with previous reports showing that CpdA suppressed the expression of various proinflammatory mediators, including TNF-a (18), IL-6 (16, 21, 34), CXCL8 (21,35), CCL2, CCL5, and CCL11 (22), with varying inhibition potencies and magnitudes. In contrast to some of these studies where dexamethasone was equally effective as CpdA in repressing inflammatory gene expression, our study is the first to report a therapeutic action of CpdA in steroid-resistant conditions.…”

“…The observation that CpdA inhibits the expression of steroid-resistant chemokines at the mRNA level (Figure 2) strongly suggests that CpdA acted at the transcriptional level. Previous reports showed that CpdA repressed the function of different transcription factors, including NF-kB or AP-1 (defined as transrepression) (19,34,40,41), STAT6 (22), and T-bet (39). We now provide the first evidence that CpdA inhibits the activation of IRF-1 by affecting its nuclear accumulation ( Figure 6).…”

“…These studies highlighted the lack of typical side effects associated with GC treatment and the equal efficacy of CpdA when compared with dexamethasone. The recent demonstration that CpdA was effective in a murine model of allergic asthma (22) strongly suggests that CpdA-sensitive pathways represent potential therapeutic targets for asthma. Using our ASM model of GC insensitivity, we found that CpdA genes by CpdA in airway smooth muscle cells.…”

“…Importantly, these beneficial effects of CpdA were not associated with the typical side effects of GC, which affect the hypothalamic-pituitary-adrenal (HPA) axis (19), levels of insulin (18,19) or glucose (17), or osteoblast differentiation (21) linked to transactivation of GCinducible genes. Recently, CpdA was found to be as effective as dexamethasone in preventing allergen responses in a murine model of asthma (22). Whether CpdA could have a therapeutic benefit in other key severe asthmatic features, such as steroid resistance, has not been investigated.…”

Mast Cells Contribute to Bleomycin-Induced Lung Inflammation and Injury in Mice through a Chymase/Mast Cell Protease 4–Dependent Mechanism

“…The BMCMC phenotype was confirmed by flow cytometry using anti-FcεRIa (MAR-I) and anti-c-Kit (2B8) Abs (eBioscience Total and differential cell counts in bronchoalveolar lavage fluids BAL and differential cell counts were performed as described previously (23). Briefly, mice were anesthetized i.p.…”