Age-related loss of CpG methylation in the tumour necrosis factor promoter

作者：Gowers Isobel R; Walters Kevin; Kiss Toth Endre; Read Robert C; Duff Gordon W; Wilson Anthony G^*

来源：Cytokine, 2011, 56(3): 792-797.

DOI：10.1016/j.cyto.2011.09.009

• DNA methylation
• Age
• TNF
• Expression
• Epigenetics

Background: Dysregulated production of TNF has been implicated in the pathogenesis and severity of inflammatory rheumatic diseases, many of which show age-related increased incidence. Ageing is also associated with changes in the immune system including higher systemic levels of pro-inflammatory cytokines. Methylation of DNA is an important regulator of gene expression and changes with age.
Objective: In this study we investigated whether the DNA methylation status of the TNF promoter changed with age in peripheral blood leucocytes and macrophages.
Methods and results: Using pyrosequencing assays we detected age-related demethylation of CpG motifs (-304, -245 and -239) in the TNF promoter in human peripheral blood cells from 312 healthy controls (0.8% per decade, confidence interval (CI) = 0.44-1.13%, p = 1 x 10(-5)) and primary monocyte-derived macrophages (MDM) from a separate population of 78 healthy controls (1.4% per decade, CI = 0.79-2.13%, p = 7 x 10(-5)). Methylation a TNF promoter fragment (-345-+154) resulted in 78% reduction of reporter gene activity compared with the unmethylated promoter construct.
Conclusions: These data suggest a potential role of accrued changes in DNA methylation in the development of age-related inflammatory diseases, such as rheumatoid arthritis and polymyalgia rheumatica, in which TNF is a pivotal mediator.

• 出版日期2011-12