engleski

Nuclear Factors and Cytokines control TFFs down regulation in tumor cell lines of the digestive tract

The acute phase response is strictly connected with modulation of gene expression. Transcriptional control of many genes is mediated by binding of diverse transcription factors to cis-acting DNA motifs in the respective promoter sequence.We aimed at analyzing such regulatory elements for the trefoil peptide genes (TFF1, TFF2 and TFF3) coding for gastroprotective peptides. We assumed them to be regulated by the proinflammatory cytokines interleukin-1β (IL1β ) and interleukin-6 (IL6), which trigger the transcriptional factors NF-κ B and C/EBPβ . 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-κ B and C/EBPβ were transiently co-expressed. We have functionally identified transcription factors NF-κ B 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. Down-regulation of intestinal trefoil factor TFF3 due to transcriptional repression by IL1β through NF-κ B 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.

TFFs; TNFa; IL1b; IL6; qPCR

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