Trefoil peptide TFF2 treatment reduces VCAM-1 expression and leukocyte recruitment in experimental intestinal inflammation

Abstract

There is evidence for a beneficial effect of trefoil peptides in animal models of gastric damage and intestinal inflammation, but the optimal treatment strategy and the mechanistic basis have not been explored thoroughly. It has been suggested that these proteins may modulate the inflammatory response. The aims of this study were to compare the protective and curative value of systemic and topical trefoil factor family (TFF)2 administration in dextran sulfate sodium-induced experimental colitis and to investigate the relationship between the therapeutic effects of TFF2 and modulation of leukocyte recruitment and expression of cell adhesion molecules. Clinical and morphologic severity of colitis was evaluated at the end of the study (Day 10). Leukocyte-endothelial cell interactions were determined in colonic venules by fluorescence intravital microscopy. The expression of cell adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and mucosal addressin cell adhesion molecule 1 (MAdCAM-1) was measured by the dual radiolabeled monoclonal antibody technique. Pretreatment with TFF2 by subcutaneous or intracolonic (ic) route ameliorated the clinical course of colitis, and the luminal route had a significantly superior effect. This beneficial effect was correlated with significant reductions in endothelial VCAM-1 but not MAdCAM-1 expression and leukocyte adhesion to intestinal venules, which returned to levels similar to those of controls. In established colitis, ic TFF2 treatment did not modify the severity of colonic lesions. In conclusion, TFF2 is useful in the treatment of colitis, and topical administration is superior to the systemic route. Reduction in adhesion molecule expression and leukocyte recruitment into the inflamed intestine contributes to the beneficial effect of this treatment.

The trefoil factor family – small peptides with multiple functionalities

“…This protective effect seemed in part to be mediated via TFF-induced expression of prostaglandin-endoperoxide synthase 2. Intra colonic instillation of hTFF2 was furthermore found to reduce expression of vascular cell adhesion molecule I (VCAM-1) on endothelial cells and leucocyte adhesion to intestinal venules in this model [170], supporting an anti-inflammatory effect of the peptides. While the DSS model may be suitable to study direct epithelial damage, it lacks the chronic inflammation and involvement of the adaptive immune system characteristic for IBD.…”

Trefoil Family Factor 2 Is Expressed in Murine Gastric and Immune Cells and Controls both Gastrointestinal Inflammation and Systemic Immune Responses

“…Several groups have reported that application of recombinant trefoils can reduce inflammatory indices in animal models of colitis (16,33,40). For example, luminal application of recombinant TFF2/spasmocytic peptide in a rat model of colitis revealed markedly accelerated colonic mucosal rebuilding and reduced inflammatory indices (40) through mechanisms that could possibly include inhibition of inducible nitric oxide synthase and NO in monocytes (17).…”

Cytokine Regulation of the Trefoil Factor Family Binding Protein GKN2 (GDDR/TFIZ1/blottin) in Human Gastrointestinal Epithelial Cells

“…These secreted peptides maintain epithelial integrity, are important for protection and wound healing. They are expressed rapidly in response to injury and are up-regulated in inflammation and ulceration [52]. TFFs are GI factors that allow the healthy mucosa to restrain inflammation and live harmoniously with its abundant flora.…”