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

1. The clinicopathological features of endotoxaemia have been ascribed to cytotoxic mediators such as tumour necrosis factor, interleukins and eicosanoids. Macrophages, particularly Kupffer cells, are an important source of these mediators. Mortality from endotoxaemia is highly age related. 2. These studies focus on the role of hepatic Kupffer cells in the increased sensitivity of old rats to bacterial endotoxins. Possible age-related changes in the production of eicosanoids and induction of gene expression and secretion of interleukin 1, tumour necrosis factor and interleukin 6 were investigated in Kupffer cells derived from both young and old animals. 3. Basal production of biological response modifiers was low in cells of both young and old rats. Lipopolysaccharide stimulated production of the same types of monokines as described for other types of macrophages, although the pattern was specific for Kupffer cells. 4. Eicosanoids, predominantly prostaglandin D2 and prostaglandin F2α, were produced mainly during the first hour after exposure to lipopolysaccharide. Endotoxin stimulated synthesis of mRNAs of interleukin 1, interleukin 6 and tumour necrosis factor α resulting in increased secretion of these cytokines into the medium. 5. Kupffer cells from both young and aged animals appear to be exquisitely sensitive to endotoxin in respect of expression of mRNA for both interleukin 1α and interleukin 1β and less sensitive with respect to interleukin 6 and tumour necrosis factor α gene expression. At relatively high lipopolysaccharide concentrations interleukin 6 was secreted in particularly large amounts. 6. The effects of ageing on any of these responses of Kupffer cells were minimal. 7. It seems unlikely that age-related changes in the synthesis and secretion of eicosanoids and cytokines by Kupffer cells are an important factor in the increased susceptibility of old rats to LPS.

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Age-Related Alterations in Basal Expression and in vitro, Tumour Necrosis Factor Alpha Mediated, Upregulation of CD11b

Gerontology ◽

10.1159/000052795 ◽

2001 ◽

Vol 47 (4) ◽

pp. 180-185 ◽

Cited By ~ 6

Author(s):

M.E. Armstrong ◽

H.D. Alexander ◽

J.L. Ritchie ◽

S.A. McMillan ◽

I.M. Rea

Keyword(s):

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Tumour Necrosis Factor Alpha ◽

Necrosis Factor Alpha ◽

Basal Expression ◽

Age Related ◽

Factor Alpha ◽

Necrosis Factor

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Substrate specificity and inducibility of TACE (tumour necrosis factor α-converting enzyme) revisited: the Ala-Val preference, and induced intrinsic activity

Biochemical Society Symposium ◽

10.1042/bss0700039 ◽

2003 ◽

Vol 70 ◽

pp. 39-52 ◽

Cited By ~ 54

Author(s):

Roy A. Black ◽

John R. Doedens ◽

Rajeev Mahimkar ◽

Richard Johnson ◽

Lin Guo ◽

...

Keyword(s):

Substrate Specificity ◽

Recent Work ◽

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Transforming Growth Factor ◽

Intrinsic Activity ◽

Converting Enzyme ◽

Tumour Necrosis Factor Α ◽

Factor Α ◽

Necrosis Factor

Tumour necrosis factor α (TNFα)-converting enzyme (TACE/ADAM-17, where ADAM stands for a disintegrin and metalloproteinase) releases from the cell surface the extracellular domains of TNF and several other proteins. Previous studies have found that, while purified TACE preferentially cleaves peptides representing the processing sites in TNF and transforming growth factor α, the cellular enzyme nonetheless also sheds proteins with divergent cleavage sites very efficiently. More recent work, identifying the cleavage site in the p75 TNF receptor, quantifying the susceptibility of additional peptides to cleavage by TACE and identifying additional protein substrates, underlines the complexity of TACE-substrate interactions. In addition to substrate specificity, the mechanism underlying the increased rate of shedding caused by agents that activate cells remains poorly understood. Recent work in this area, utilizing a peptide substrate as a probe for cellular TACE activity, indicates that the intrinsic activity of the enzyme is somehow increased.

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