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

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=1×10(-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=7×10(-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.