Trefoil Peptide Gene Expression in Gastrointestinal Epithelial Cells in Inflammatory Bowel Disease

Abstract

Trefoil peptides are a growing group of proteins with interesting structural and functional properties. We have defined the pattern of trefoil peptide gene expression in the ulceration-associated cell lineage (UACL) and in the nearby mucosa in Crohn's disease. In the UACL, human spasmolytic polypeptide (hSP) mRNA is expressed in the acinar and proximal duct cells, while pS2 mRNA and peptide are found in the distal duct cells and in the surface cells. In adjacent mucosa, pS2 mRNA and protein are expressed by goblet cells, with the pS2 peptide concentrated in the area of the Golgi and also in the theca. Ultrastructural immunolocalisation showed the pS2 to be co-packaged in the mucous cell granules before being secreted into the intestinal lumen. In addition, pS2 peptide was demonstrated in local neuroendocrine cells and was also co-packaged with the neuroendocrine granules. The crypts associated with the UACL also showed marked neuroendocrine cell hyperplasia. We conclude that pS2 peptide is secreted locally into the viscoelastic coat covering the intestinal mucosa which surrounds Crohn's disease ulcers. In addition, it is clear that intestinal goblet cells, in addition to producing mucins, are a rich source of regulatory peptides. Moreover, pS2 is clearly co-packaged with neurosecretory granules, which are released through basal and lateral membranes so that the contained peptides can act in a paracrine manner. These findings are interpreted in terms of the epidermal growth factor/urogastrone released by the UACL, stimulating pS2 gene expression in surrounding cells. The co-packaging of the same secretory protein in both mucous and neuroendocrine granules, which have markedly different functions, is highly unusual and indicates an important role for pS2 in the secretory process itself, or as a ligand delivered to its receptor via quite different routes. We conclude that the trefoil peptides are widely distributed in the intestine in inflammatory bowel disease, and are thus of considerable potential functional importance.