Neurotensin is a proinflammatory neuropeptide in colonic inflammation
Ignazio Castagliuolo, Chi-Chung Wang, Leyla Valenick, Asiya Pasha, Sigfus Nikulasson, Robert E. Carraway, Charalabos Pothoulakis
Ignazio Castagliuolo, Chi-Chung Wang, Leyla Valenick, Asiya Pasha, Sigfus Nikulasson, Robert E. Carraway, Charalabos Pothoulakis
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Neurotensin is a proinflammatory neuropeptide in colonic inflammation

Abstract

The neuropeptide neurotensin mediates several intestinal functions, including chloride secretion, motility, and cellular growth. However, whether this peptide participates in intestinal inflammation is not known. Toxin A, an enterotoxin from Clostridium difficile, mediates pseudomembranous colitis in humans. In animal models, toxin A causes an acute inflammatory response characterized by activation of sensory neurons and intestinal nerves and immune cells of the lamina propria. Here we show that neurotensin and its receptor are elevated in the rat colonic mucosa following toxin A administration. Pretreatment of rats with the neurotensin receptor antagonist SR-48,692 inhibits toxin A–induced changes in colonic secretion, mucosal permeability, and histologic damage. Exposure of colonic explants to toxin A or neurotensin causes mast cell degranulation, which is inhibited by SR-48,692. Because substance P was previously shown to mediate mast cell activation, we examined whether substance P is involved in neurotensin-induced mast cell degranulation. Our results show that neurotensin-induced mast cell degranulation in colonic explants is inhibited by the substance P (neurokinin-1) receptor antagonist CP-96,345, indicating that colonic mast activation in response to neurotensin involves release of substance P. We conclude that neurotensin plays a key role in the pathogenesis of C. difficile–induced colonic inflammation and mast cell activation.

Authors

Ignazio Castagliuolo, Chi-Chung Wang, Leyla Valenick, Asiya Pasha, Sigfus Nikulasson, Robert E. Carraway, Charalabos Pothoulakis

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Increased NTR1 mRNA expression during toxin A–induced colitis in rats. R...
Increased NTR1 mRNA expression during toxin A–induced colitis in rats. Rat colonic loops were exposed to either toxin A or buffer. After 1 h, animals were sacrificed, and colonic tissues were processed for in situ hybridization using 383-base-digoxigenin–labeled antisense riboprobe encoding for the NTR1 mRNA. Tissues were examined by confocal microscopy. (a) Section from a rat colon exposed only to buffer shows the presence of little hybridization signal in the epithelial layer and in cells of the lamina propria. (b) Colon exposed for 1 h to toxin A shows increased signal for the NTR1 mRNA primarily in intestinal epithelial cells (arrows), but also in cells of the lamina propria (arrowheads). (c) Colon from toxin A–exposed loop hybridized with a sense riboprobe encoding for the NTR1 mRNA shows absence of specific signal. Results are representative of three experiments for each experimental condition. Scale bar: 50 μm. NTR1, NT receptor-1.