trypsinogen and Irritable-Bowel-Syndrome

Proteases are key mediators of pain and altered enteric neuronal signalling, although the types and sources of these important intestinal mediators are unknown. We hypothesised that intestinal epithelium is a major source of trypsin-like activity in patients with IBS and this activity signals to primary afferent and enteric nerves and induces visceral hypersensitivity.. Trypsin-like activity was determined in tissues from patients with IBS and in supernatants of Caco-2 cells stimulated or not. These supernatants were also applied to cultures of primary afferents. mRNA isoforms of trypsin (. We showed that stimulated intestinal epithelial cells released trypsin-like activity specifically from the basolateral side. This activity was able to activate sensory neurons. In colons of patients with IBS, increased trypsin-like activity was associated with the epithelium. We identified that trypsin-3 was the only form of trypsin upregulated in stimulated intestinal epithelial cells and in tissues from patients with IBS. Trypsin-3 was able to signal to human submucosal enteric neurons and mouse sensory neurons, and to induce visceral hypersensitivity in vivo, all by a protease-activated receptor-2-dependent mechanism.. In IBS, the intestinal epithelium produces and releases the active protease trypsin-3, which is able to signal to enteric neurons and to induce visceral hypersensitivity.

Topics: Animals; Caco-2 Cells; Case-Control Studies; Colon; Culture Media, Conditioned; Dipeptides; Enteric Nervous System; Epithelial Cells; Female; Ganglia, Spinal; Humans; Hypersensitivity; Intestinal Mucosa; Irritable Bowel Syndrome; Isoxazoles; Lipopolysaccharides; Male; Mice; Microscopy, Confocal; Neurons, Afferent; Permeability; Rats; Receptor, PAR-2; RNA, Messenger; Trypsin; Trypsinogen; Up-Regulation