DNA Methylation and the Expression of IL-4 and IFN-γ Promoter Genes in Patients with Bronchial Asthma

Abstract

Although CpG methylation is thought to be a negative regulator of gene transcription, its relationship with cytokine expression remains unclear. Interleukin (IL)-4 and interferon (IFN)-gamma are major cytokines that affect the differentiation of naïve CD4+ T lymphocytes into the Th1 and Th2 lineage. We used bisulfite deoxyribonucleic acid modification and sequencing to examine the relationship between CpG methylation and IL-4 and IFN-gamma gene expression before and after allergen stimulation in human CD4+ T lymphocytes from sensitized hosts. In naïve cells, the CpGs in the promoter regions were methylated largely in both the IL-4 and IFN-gamma genes. After Dermatophagoides pteronyssinus/Dermatophagoides farinae stimulation, the degree of unmethylation in the IL-4 gene increased in cells from patients with bronchial asthma. After phytohemagglutinin stimulation, the degree of unmethylation increased in cells from nonallergic control subjects. The concentration of IL-4 was strongly correlated with the degree of unmethylation in the patient group. These data suggest that CpGs located at -80 of the IL-4 gene and at -295, -186, and +122 of the IFN-gamma gene have regulatory activities important for cytokine expression. We conclude that the stimulation of CD4+ T lymphocytes causes considerable increases in the degree of unmethylation and that in sensitized hosts, the extent of unmethylation correlates with the concentration of IL-4.

Enhanced Demethylation of Interferon-.GAMMA. Gene Promoter in Peripheral Blood Mononuclear Cells Is Associated with Acute-on-Chronic Hepatitis B Liver Failure

“…These results suggest that methylation of the IFN-γ promoter may regulate the IFN-γ synthesis in HBV infection. Our results are consistent with published findings that epigenetic methylation status of IFN-γ may play a mechanistic role in the modulation of cytokine secretion in the mucosa (Rivkah et al 2009) and patients with bronchial asthma (Kwon et al 2008). The exact mechanisms leading to altered methylation of IFN-γ promoter are not known.…”

“…Recently, HBV has been found to induce over expression of DNMTs, which might lead to methylation of host CpG islands and inhibition of viral gene replication in natural infection model and temporary transfection model (Vivekanandan et al 2010). Therefore, according to the present results and previous studies (Mikovits et al 1998;Ohta et al 2000;Lee et al 2001;Lee et al 2002;Kwon et al 2008;Rivkah et al 2009;Vivekanandan et al 2010), we speculate that hepatitis B virus might have the ability to induce methylation IFN-γ promoter which may down-regulate the IFN-γ secretion. However, further research needs to be performed to confirm this hypothesis.…”

Pediatric Obesity-Related Asthma: The Role of Metabolic Dysregulation

“…139 Similarly, hypomethylation of DNA at the IL-4 gene promoter and hypermethylation of the IFNγ promoter have been observed in children with atopic asthma. 143 Genome-wide studies have also identified differential methylation of several genes associated with atopic inflammation among asthmatics. 141 However, only 1 study defined differences in DNA methylation among children with obesity-related asthma compared with children with normal-weight asthma, obesity without asthma, and healthy controls.…”

Genetic Diversity, Epigenetic Reprogramming and Environmental Factors: Leading Directions in the Study of the Complex Human Diseases

“…(38)(39)(40)(41) The state of genome instability in connection with the violation of DNA methylation processes appears to be the fundamental basis for the manifestation and/or maintenance of the pathological process in carcinogenesis, atherosclerosis, autoimmune process. (42)(43)(44)(45) The phenomenon of total hypomethylation, which is the most important indicator of genome instability, is defined quite clearly in three acute conditions of the organism: at the very beginning of embryonic development, at the final stages of ontogeny of the organism in the process of its aging and, finally, in the process of malignant transformation. Generally, during the aging process, global hypomethylation of DNA occurs in a repetitive sequence pattern that may promote genomic instability.…”