Effect of Lipopolysaccharide on Glucocorticoid Receptor Function in Control Nasal Mucosa Fibroblasts and in Fibroblasts from Patients with Chronic Rhinosinusitis with Nasal Polyps and Asthma (original) (raw)
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The Journal of Immunology, 2007
Although it is widely accepted that glucocorticoids (GC) are a mainstay of the treatment of diseases characterized by airway inflammation, little is known about the effects of GC on local innate immunity. In this article, we report that respiratory epithelial cells manifested a local "acute phase response" after stimulation with TLR activation and TNF-␣ and that GC spared or enhanced the epithelial expression of molecules that are involved in host defense, including complement, collectins, and other antimicrobial proteins. As expected, GC inhibited the expression of molecules responsible for inflammation such as cytokines (IFN and GM-CSF) and chemokines (RANTES and IL-8). Studies using Western blotting, EMSA, and functional analysis indicated that the selective effects of GC are mediated through activation of the transcription factor C/EBP. Knockdown of C/EBP by small interfering RNA blocked the enhancement by GC of host defense molecule expression but had no effect on inflammatory gene expression. These results suggest that GC spare or enhance local innate host defense responses in addition to exerting anti-inflammatory actions. It is possible that the known ability of GC to reduce the exacerbation of diseases in which infectious organisms serve as triggering factors (e.g., asthma, allergic bronchopulmonary aspergillosis, and chronic obstructive pulmonary disease) may result in part from enhanced innate immune responses in airway mucosa.
Quantitative Analysis of Activated Glucocorticoid Receptors in Nasal Polyps
Nihon Bika Gakkai Kaishi (Japanese Journal of Rhinology), 2006
Objective: The purpose of our study was to measure the activated glucocorticoid receptor (GR) protein level in the nuclei of nasal polyp cells and compare the results in nasal polyposis patients with chronic rhinosinusitis alone and with chronic rhinosinusitis associated with asthma, before and after glucocorticoid (GC) therapy. Methods: We used enzyme-linked immunosorbentassay (ELISA) techniques to quantitatively measure the activated-GR protein level in the nuclei of the nasal polyp cells. Nasal polyp tissues were obtained from patients with chronic rhinosinusitis alone and with both chronic rhinosinusitis and bronchial asthma. In the latter, polyp tissues were separately obtained before and after GC therapy. Results: Our data showed no significant differences between the activated-GR protein level of the nasal polyposis patients with chronic rhinosinusitis alone and with both chronic rhinosinusitis and bronchial asthma before GC therapy. However, the activated-GR protein level was significantly upregulated after GC therapy in the patients with both chronic rhinosinusitis and bronchial asthma. Conclusion: The result of our research clearly showed that GCs upregulated the activated-GR protein level in the nuclei of nasal polyp cells and that the upregulation is essential for the anti-inflammatory action of GCs.
Biochemistry and Biophysics Reports, 2016
Corticosteroid resistance is one of major barriers to effective management of chronic inflammatory respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and severe asthma. These patients often experience exacerbations with viral and/or bacterial infection, which may cause continuous corticosteroid insensitive inflammation. In this study, we observed that repeated exposure of lipopolysaccharide (LPS) intranasally attenuated the anti-inflammatory effects of the corticosteroid fluticasone propionate (FP) on neutrophils and CXCL1 levels in bronchoalveolar lavage (BAL) fluid in an in vivo murine model. Histone deacetylase-2 (HDAC2) and NF-E2 related factor 2 (Nrf2) levels in lungs after LPS administration for 3 consecutive days were significantly decreased to 38.9 76.3% (mean7 SEM) and 77.572.7% of the levels seen after only one day of LPS exposure, respectively. In addition, 3 days LPS exposure resulted in an increase of Akt phosphorylation, indicating activation of the phosphoinositide-3kinase (PI3K) pathway by 4-fold in lungs compared with 1 day of exposure. Furthermore, combination treatment with theophylline and FP significantly decreased the neutrophil accumulation and CXCL1 concentrations in BAL fluid from 22.5 7 1.8 Â 10 4 cells/mL and 214.67 20.6 pg/mL to 7.970.5 Â 10 4 cells/mL and 61.9 713.3 pg/mL, respectively. Combination treatment with IC87114, a selective PI3Kδ inhibitor, and FP also significantly decreased neutrophils and CXCL1 levels from 16.8 7 0.7 Â 10 4 cells/mL and 182.4 7 4.6 pg/mL to 5.97 0.3 Â 10 4 cells/mL and 71.47 2.7 pg/mL, respectively. Taken together, repeated exposure of LPS causes corticosteroid-insensitive airway inflammation in vivo, and the corticosteroid-resistance induced by LPS is at least partly mediated through the activation of PI3Kδ, resulting in decreased levels of HDAC2 and Nrf2. These findings provide a potentially new therapeutic approach to COPD and severe asthma.
In vivo (Athens, Greece)
Glucocorticoids (GCs) bind to the cellular glucocorticoid receptors (GRs) to exert anti-inflammatory and immunosuppressive actions. We investigated the changes in the expressions of the two GR isoforms, GR-alpha and GR-beta, in nasal polyps treated with GC. Immunofluorescent staining revealed prominent expression of GR-alpha in the inflammatory cell infiltrate in the polyps obtained from patients with chronic sinusitis and bronchial asthma. Furthermore, while the expression of GR-alpha was significantly reduced following GC treatment, that of GR-beta remained unchanged. The results of real-time PCR also revealed that the prominent expression of GR-alpha mRNA in the polyps decreased following GC treatment, while the expression of GR-beta mRNA remained unchanged. The observations indicate that GR-alpha may play the major role in the inflammation associated with nasal polyps and the ratio of the expression level of GR-beta to that of GR-alpha may serve as a useful index of the clinical...
Respiratory Medicine, 2003
The lower sensitivity of the inflamed nasal mucosa to glucocorticoids might be related to an increased expression of the glucocorticoid receptor (GR) beta isoform.We investigated GRa and GRb mRNA expression in epithelial cells from nasal mucosa and nasal polyps.GRa mRNA was at least1000 times more expressed than GRb mRNA in both tissues.GRb expression (mean7SEM of 10 3 cDNA copies/mg of total RNA) was higher in nasal polyps (1.1570.19; n=27; Po0.01) than in nasal mucosa (0.6270.10; n=32). Nasal polyps with43% of inflammatory cells had higher GRb levels (1.4070.29; n=16) than both nasal mucosa (Po0.01) and polyps with r3% of inflammatory cells (0.8070.18; n=11; Po0.05).No difference in GRbexpression was found between nasalmucosa and polyps with r 3% of inflammatory cells. GRb expression correlated with the inflammatory cell number, especially with mast cells (r=0.50, Po0.0001). There was no difference in GRa mRNA expression between nasal mucosa and nasal polyps. In summary,GRa is far more expressed than GRbin bothtissues.The increased expression of GRb may be related to the presence of inflammatory cells.
Glucocorticoid actions in human bronchial epithelial cells
Neutrophil recruitment 103,105,106 TNF-a Augment inflammation 139 GM-CSF Prolong eosinophil/neutrophi1 survival 15,131,132 Increase eosinophil activation MCP-1 Monocyte/eosinophil recruitment 108 RANTES Eosinophil, monocyte, basophil, 17,110,111 T cell recruitment GROa Neutrophil recruitment 108 GRay Neutrophil recruitment 108 PAF Eosinophil recruitment 113 MIP-2 Neutrophil recruitment 114 TGF-p Reduce inflammation 140,141