engleski

Tumour necrosis factor alpha and nuclear factor kappaB inhibit transcription of human TFF3 encoding a gastrointestinal healing peptide

Background & Aims: Damage to the gastrointestinal mucosa results in an up-regulation of the trefoil factor family peptides TFF1, TFF2 and TFF3 connected with protective, curative, and tumour suppressive functions. We suspected TFF genes to be regulated by the proinflammatory cytokine TNF-a via transcription factor NF-kB. Methods: After TNF-a stimulation, expression of TFF genes was analysed by quantitative real-time RT-PCR and by reporter gene assays using wild type and mutated TFF promoter in gastrointestinal cell lines HT-29 and KATO III. NF-kB and a constitutive repressive form of IkB were transiently co-expressed. In vivo, morphological changes, expression of TFF3, mucins and NF-kB was monitored by immunohistochemistry in a rat model of TNBS-induced colitis. Results: TNF-a stimulation evoked permanent up to 10-fold reduction of TFF3 expression in colonic tumour cell line HT-29 and 2.5-fold reduction of TFF1. In gastric cell line KATO III 2.5-fold reduction of TFF3 expression was noticed at late stage after stimulation and was returned to normal level. A down-regulation of reporter gene transcription of TFF 3 was observed by both TNF-a and NF-kB, and was reversible by IkB. In vivo, increase of epithelial NF-kB expression coincided with reduced TFF3 expression during the acute phase of experimental colitis. Conclusions: Down-regulation of intestinal trefoil factor TFF3 is caused by transcriptional repression through TNF-a and NF-kB activation in vitro. In inflammatory bowel disease reduced TFF3 activity may contribute to ulceration and decreased wound healing.

TNF-alpha ; NF-kappaB ; TFF3 gene

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