TFF3 modulates NF-{kappa}B and a novel negative regulatory molecule of NF-{kappa}B in intestinal epithelial cells via a mechanism distinct from TNF-{alpha}.
Trefoil factor 3 (intestinal trefoil factor) is a cytoprotective factor in the gut. Herein we compared the effect of trefoil factor 3 with tumor necrosis factor-alpha on 1) activation of NF-kappaB in intestinal epithelial cells; 2) expression of Twist protein (a molecule essential for downregulation of nuclear factor-kappaB activity in vivo); and 3) production of interleukin-8. We showed that Twist protein is constitutively expressed in intestinal epithelial cells. Tumor necrosis factor-alpha induced persistent degradation of Twist protein in intestinal epithelial cells via a signaling pathway linked to proteasome, which was associated with prolonged activation of NF-kappaB. In contrast to tumor necrosis factor, trefoil factor 3 triggered transient activation of NF-kappaB and prolonged upregulation of Twist protein in intestinal epithelial cells via an ERK kinase-mediated pathway. Unlike tumor necrosis factor-alpha, transient activation of NF-kappaB by trefoil factor 3 is not associated with induction of IL-8 in cells. To examine the role of Twist protein in intestinal epithelial cells, we silenced the Twist expression by siRNA. Our data showed that trefoil factor 3 induced interleukin-8 production after silencing Twist in intestinal epithelial cells. Together, these observations indicated that 1) trefoil factor 3 triggers a diverse signal from tumor necrosis factor-alpha on the activation of NF-kappaB and its associated molecules in intestinal epithelial cells; and 2) trefoil factor 3-induced Twist protein plays an important role in the modulation of inflammatory cytokine production in intestinal epithelial cells.
Zhu
Ya-Qin
YQ
Molecular and Cellular Pathobiology Program, Children's Memorial Research Center, Children's Memorial Hospital, 2300 Children's Plaza, Box 217, Chicago, IL 60614, USA. yaqin-zhu@northwestern.edu
Tan
Xiao-Di
XD
D000818:Animals; D002460:Cell Line; D004847:Epithelial Cells / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D016209:Interleukin-8; D007413:Intestinal Mucosa / Q000502:physiology; D009077:Mucins / Q000502:physiology*; D009124:Muscle Proteins / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D010455:Peptides; D014157:Transcription Factors / Q000502:physiology*; D000071165:Trefoil Factor-3; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D051879:Twist-Related Protein 1
D016209:Interleukin-8; D009077:Mucins; D009124:Muscle Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D010455:Peptides; C082495:TFF3 protein, human; C103173:TWIST1 protein, human; D014157:Transcription Factors; D000071165:Trefoil Factor-3; D014409:Tumor Necrosis Factor-alpha; D051879:Twist-Related Protein 1