The NR3C1 Glucocorticoid Receptor Gene Polymorphisms May Modulate the TGF-beta mRNA Expression in Asthma Patients

摘要

Glucocorticosteroids (GCs) are basic drugs in therapy of a number of diseases, including chronic diseases of the respiratory system. They are the most important anti-inflammatory drugs in the treatment of asthma. GCs after binding to the glucocorticoid receptor (GR) form the complex (transcription factor), which acts on promoter and regulatory parts of genes enhancing the expression of anti-inflammatory proteins and decreasing the proinflammatory protein synthesis, including numerous cytokines mediating inflammation in the course of asthma. Non-sensitivity or resistance to GCs favours an increase in the TGF-beta expression. This cytokine plays a central role in asthma inducing fibroblast differentiation and extracellular matrix synthesis. TGF-beta isoforms, 1, 2 and 3, are located on chromosome 19q13, 1q41 and 14q24, respectively. GCs reduce TGF-beta 1 and TGF-beta 2 production and significantly decrease the expression of upregulated TGF-beta 1 and TGF-beta 2 mRNA induced by exogenous TGF-beta. In asthma, TGF-beta may play a role in the development of the peribronchiolar and subepithelial fibrosis, which contributes to a significant clinical exacerbation of asthma. Therefore, it is possible that NR3C1 glucocorticoid receptor gene polymorphisms could exert varied effects on the TGF-beta mRNA expression and fibrotic process in lungs of asthmatic patients. The aim of the study was to evaluate the impact of polymorphic forms (Tth111I, BclI, ER22/23EK, N363S) of the NR3C1 gene on the level of the TGF-beta 1 mRNA expression. A total of 173 patients with asthma and 163 healthy volunteers participated in the study. Genotyping of Tth111I, BclI, ER22/23EK, and N363S polymorphisms of the NR3C1 gene was performed by using PCR-HRM and PCR-RFLP techniques. TGF-beta mRNA was assessed by real time RT-PCR. Tth111I SNP significantly (p = 0.0115) correlated with the TGF-beta 1 mRNA expression level. The significance of AA and GG genotypes of Tth111I SNP in increasing and decreasing the level of the TGF-beta 1 mRNA expression was demonstrated. Both BclI SNP and ER22/23EK SNP did not affect the expression level of the cytokine analysed. The N363S SNP AA genotype of NR3C1 gene statistically significantly influenced the increase in the level of the TGF-beta 1 mRNA expression. Thus, SNPs of NR3C1 gene play an important regulatory function in the bronchi of patients suffering from asthma. In the case of the occurrence of Tth111I and N363S polymorphic forms of the gene studied, a reduced ability of GCs to inhibit the TGF-beta 1 expression can be observed.