Down-regulation of <i>TFF</i> Expression in Gastrointestinal Cell Lines by Cytokines and Nuclear Factors

Abstract

Background and Aims: Trefoil peptides (TFF1, TFF2 and TFF3) are acute phase proteins up-regulated in response to gastrointestinal mucosal damage. They promote cell migration, protect and heal the mucosa and may function as tumorsuppressors. We assumed them to be regulated by the proinflammatory cytokines interleukin-1β (IL1β) and interleukin-6 (IL6), which trigger the transcriptional factors NF-ĸB and C/EBPβ. Methods: Following IL1β and IL6 stimulation, expression of TFF genes was analyzed in gastrointestinal cell lines HT-29 and KATO III by reporter gene assays using TFF promoter constructs and by quantitative real-time PCR. NF-ĸB and C/EBPβ were transiently co-expressed. Results: We have functionally identified transcription factors NF-ĸB and C/EBPβ to inhibit transcription of human TFF genes. Down-regulation of TFF transcription is also observed by IL1β and IL6, suggesting crosstalk with or in response to the immune system. IL1β and IL6 caused a 3- to 11-fold reduction in TFF mRNA expression, displayed in real-time PCR. Conclusions: Down-regulation of intestinal trefoil factor TFF3 due to transcriptional repression by IL1β through NF-ĸB as well as by IL6 through C/EBPβ activation in vitro may reflect the situation in vivo and may contribute to ulceration and decreased wound healing during inflammatory bowel disease. Additionally, IL1 and IL6 over-expression in chronic gastritis may lead to mucosal damage and gastric carcinogenesis through transcriptional repression of TFF1 and TFF2.

Cofactor of BRCA1: A Novel Transcription Factor Regulator in Upper Gastrointestinal Adenocarcinomas

“…The decline of TFF1 expression during upper gastrointestinal carcinogenesis is well documented (10,21,29). Nearly 50% of all UGCs tested show marked reduction of TFF1 expression (9).…”

“…3A). The mutants serially eliminated consensus-binding sites of transcription factors that were known to alter TFF1 expression (7,16,20,21). Transient transfection of AGS gastric adenocarcinoma cells was followed by luciferase assays.…”

“…3A; refs. 7,[20][21][22]. As COBRA1 does not have a DNA-binding domain, it acts solely as a cofactor.…”

Multidisciplinary approach to understand the pathogenesis of gastric cancer

“…They are upregulated around areas of epithelial damage, ulceration, and neoplasia [79] . IL-1 and IL-6 overexpression in chronic gastritis may lead to mucosal damage and gastric carcinogenesis through transcriptional repression of TFF1 and TFF2 [80] . TFF1 knockout mice developed multiple gastric adenomas and carcinomas, suggesting that TFF1 is a gastric-specific tumorsuppressor gene [81] .…”

Review article: regulation of TFF1 (pS2) expression in gastric epithelial cells

“…As TFF2 expression was also found to be significantly upregulated by GATA-6, it can be assumed that GATA proteins play an important role in the expression of gastric TFFs. Dossinger et al 31 investigated the effect of proinflammatory cytokines (IL-1b and IL-6) on the expression of TFF1 in gastric and colonic cell lines. These cytokines were found to downregulate TFF expression.…”