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

Abstract:

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.

journal_name

Cytokine

journal_title

Cytokine

authors

Gowers IR,Walters K,Kiss-Toth E,Read RC,Duff GW,Wilson AG

doi

10.1016/j.cyto.2011.09.009

subject

Has Abstract

pub_date

2011-12-01 00:00:00

pages

792-7

issue

3

eissn

1043-4666

issn

1096-0023

pii

S1043-4666(11)00745-9

journal_volume

56

pub_type

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