Trefoil Factor Peptides and Gastrointestinal Function

Abstract

Trefoil factor (TFF) peptides, with a 40-amino acid motif and including six conserved cysteine residues that form intramolecular disulfide bonds, are a family of mucin-associated secretory molecules mediating many physiological roles that maintain and restore gastrointestinal (GI) mucosal homeostasis. TFF peptides play important roles in response to GI mucosal injury and inflammation. In response to acute GI mucosal injury, TFF peptides accelerate cell migration to seal the damaged area from luminal contents, whereas chronic inflammation leads to increased TFF expression to prevent further progression of disease. Although much evidence supports the physiological significance of TFF peptides in mucosal defenses, the molecular and cellular mechanisms of TFF peptides in the GI epithelium remain largely unknown. In this review, we summarize the functional roles of TFF1, 2, and 3 and illustrate their action mechanisms, focusing on defense mechanisms in the GI tract.

Keywords: GI mucosal defense; TFF signaling; cell migration; homeostasis; immune system; mucin.

Figure 1

Candidate TFF pathways in epithelial repair. In response to acute epithelial injury, neighboring healthy epithelial cells start to rapidly migrate toward the damaged site, resulting in force to extrude injured cells and simultaneously cover the denuded area. TFF peptides, mucus, and cellular debris form a mucoid cap to cover the injured area to protect against further injury and potentially partake in promoting recovery directly. TFF peptides facilitate GI epithelial restitution by stimulating cell migration and inhibiting apoptosis of the migrating cells. The motogenic effect of TFF peptides can be mediated (directly or indirectly) by EGFR, CXCRs, or other receptors. This is followed by the stimulation of the Rho-family GTPase to promote cell migration by altering the cytoskeleton and tight junctions as well as cell adhesions. Either upstream or downstream of the above signaling cascades, TFF peptides can also stimulate calcium mobilization resulting in enhanced cell migration. TFF peptides may directly or indirectly affect the NHE2 exchanger, as NHE2 activity is crucial for TFF-driven cell migration (at least in the stomach). Abbreviations: CXCR, C-X-C chemokine receptor; EGFR, epidermal growth factor receptor; GI, gastrointestinal; NHE, sodium hydrogen exchanger; TFF, trefoil factor.

Figure 2

Candidate TFF pathways in GI inflammation. Goblet cells produce and secrete TFF3 along with MUC2 into the lumen within the intestine, whereas gastric mucus cells secrete TFF1, which is present with MUC5AC. Although TFF2/MUC6 is also present within the stomach, Helicobacter pylori is shown to primarily interact with MUC5AC/TFF1 in the gastric lumen. The response to chronic inflammation within both the stomach and the intestine acts in a similar manner where cytokine stimulation causes TFF upregulation or downregulation, or metaplasia leads to the increase of TFF-secreting cell differentiation and results in a negative feedback to the immune response. Abbreviations: GI, gastrointestinal; MUC, mucin; NF-κB, nuclear factor kappa- B; TFF, trefoil factor.