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Neurotensin is a proinflammatory neuropeptide in colonic inflammation
Ignazio Castagliuolo, … , Robert E. Carraway, Charalabos Pothoulakis
Ignazio Castagliuolo, … , Robert E. Carraway, Charalabos Pothoulakis
Published March 15, 1999
Citation Information: J Clin Invest. 1999;103(6):843-849. https://doi.org/10.1172/JCI4217.
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Article

Neurotensin is a proinflammatory neuropeptide in colonic inflammation

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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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Figure 3

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Increased NTR1 protein expression during toxin A colitis in rats. Rat co...
Increased NTR1 protein expression during toxin A colitis in rats. Rat colonic loops were injected with either toxin A (5 μg) or buffer (control). Animals were sacrificed after 2 h, and colonic tissues were processed for immunohistochemical detection using a rabbit polyclonal antibody directed against the NH2-terminal amino acids 1–28 and 50–69 of the rat NTR1 receptor. Sections were examined by confocal microscopy. (a) Buffer-exposed colon (2 h). (b) Toxin A–exposed colon (2 h). (c) Toxin A–exposed colon (2 h) incubated with the NTR1 antiserum, which was preincubated with an excess of the two NH2-terminal peptides of the NTR1 described above. (d) Higher magnification of b. Note the presence of signal for NTR1 in the colonic mucosa, in particular the colonic epithelial cells (arrows in b and d), and in cells in the lamina propria (arrowhead). Note also the increased immunoreactivity after 2 h exposure to toxin A (b) compared with control (a). Preabsorption of the NTR1 antiserum with an excess of the receptor peptides used to generate the antibody causes complete disappearance of positive staining in toxin A–exposed colon (c). Results are representative of three experiments for each experimental condition. Scale bar: 50 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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