TFF3 modulates NF-κB and a novel negative regulatory molecule of NF-κB in intestinal epithelial cells via a mechanism distinct from TNF-α

• Published in: American Journal of Physiology: Cell Physiology 2005-11, Vol.289 (5), p.C1085-C1093
• Main Authors: Zhu, Ya-Qin, Tan, Xiao-Di
• Format: Article
• Language: English
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00185.2005

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-α on 1) activation of NF-κB in intestinal epithelial cells; 2) expression of Twist protein (a molecule essential for downregulation of nuclear factor-κB activity in vivo); and 3) production of interleukin-8. We showed that Twist protein is constitutively expressed in intestinal epithelial cells. Tumor necrosis factor-α 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-κB. In contrast to tumor necrosis factor, trefoil factor 3 triggered transient activation of NF-κB and prolonged upregulation of Twist protein in intestinal epithelial cells via an ERK kinase-mediated pathway. Unlike tumor necrosis factor-α, transient activation of NF-κB 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-α on the activation of NF-κB 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.