Tumour necrosis factor-α in Barrett's oesophagus: a potential novel mechanism of action

Abstract

Barrett's metaplasia (BM) is an early lesion in the progression from oesophageal inflammation through dysplasia to the development of Barrett's adenocarcinoma (BA). Previous work indicates that BM and BA are associated with reduced E-cadherin expression and increased cytoplasmic/nuclear pools of its associated protein b-catenin. b-catenin participates in Wnt signalling and activates oncogene transcription by complexing with T-cells factors (TCF). One such oncogene is c-myc. We have previously shown that TNF-a can downregulate E-cadherin expression. Here, we assess TNF-a expression in Barrett's metaplasia and examine if TNF-a can promote b-catenin mediated transcription of oncogenes in a gastrointestinal model system. Employing immunohistochemistry and Western blot analysis of oesophageal tissue, epithelial expression of TNF-a increases with progression along the metaplasia -dysplasia -carcinoma sequence (P50.001). b-catenin mediated transcription was then assessed in TNF-a stimulated cell lines using the TOPFLASH reporter system whilst cmyc expression was assessed by real time PCR. In a columnar intestinal cell model, TNF-a induces c-myc expression which is induced via b-catenin mediated transcription (P50.05). This b-catenin mediated transcription is independent of NF-kB activation. Thus, TNF-a is up-regulated in the progression of Barrett's oesophagus and b-catenin mediated transcription of cmyc is a novel pathway whereby elevated levels of TNF-a may lead to oncogene transcription and altered biology in gastrointestinal epithelia and metaplasia.

Transforming Growth Factor-β1-Mediated Slug and Snail Transcription Factor Up-Regulation Reduces the Density of Langerhans Cells in Epithelial Metaplasia by Affecting E-Cadherin Expression

“…Consistent with this hypothesis, an altered expression of several soluble factors such as TGF-␤, tumor necrosis factor (TNF)-␣, and interleukin (IL)-10 has been observed in esophageal and cervical EpM. 10,44,45 Similarly, the expression of E-cadherin, which is necessary for the retention of antigen-presenting cells in epithelial tissues, 36 is decreased in gastric and esophageal areas of intestinal metaplasia compared to normal epithelium. 14,46 LCs are antigen-presenting cells that play a key role in the immunosurveillance of epidermis and mucosal surfaces.…”

Elevated tumour interleukin-1β is associated with systemic inflammation: a marker of reduced survival in gastro-oesophageal cancer

“…These findings are supported by Yuan et al (2000) who investigated IL-8 mRNA concentrations in tumour tissue and adjacent normal lung tissue among patients with nonsmall-cell lung cancer and also found increased cytokine expression within the tumour tissue. Other groups have similarly demonstrated increased tissue cytokine concentrations associated with progression along the metaplasia -dysplasia -carcinoma sequence in Barrett's oesophagus (Tselepis et al, 2002;Dvorakova et al, 2004).…”

The differences of sarcopenia-related phenotypes: effects of gender and population

“…The increased plasma TC in male rats during exercise is at least partially a result of lactate's effect on the secretion of testosterone [30,31], and testosterone may suppress the expression of proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1 [8,32]. In experimental models, these proinflammatory cytokines disrupt normal insulin action in fat and muscle cells, and this may be the major factor in causing the whole body IR observed in patients with visceral adiposity [47]. In addition, cholesterol, a precursor of testosterone, comes for about one third from the dietary intake and for about two thirds from endogenous synthesis from unburned food metabolites [27]; thus, different cholesterol intake from food may also impose a significant impact on plasma TC and consequently the IS in skeletal muscle.…”