A neurotensin antagonist, SR 48692, inhibits colonic responses to immobilization stress in rats.

Castagliuolo, Ignazio; Leeman, Susan E.; Bartolák‐Suki, Erzsébet; Nikulásson, Sigfús; Qiu, Bosheng; Carraway, Robert E.; Pothoulakis, Charalabos

doi:10.1073/pnas.93.22.12611

Cited by 74 publications

(52 citation statements)

References 37 publications

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“…These results are in agreement with those of recent studies showing that sulfated oligosaccharides on MUC5B function as adhesion molecules for H. pylori (42,43). The findings of our study resemble the results of animal studies investigating the effects of acute stressors (ie, water immersion and restraint stress) on the activity of secretory cells in the colon, stomach, and nasopharynx (63)(64)(65)(66)(67)(68)(69)(70)(71). These studies demonstrated robust effects of acute stress on mucin release, synthesis, and glycosylation (a process in which carbohydrate structures on proteins are formed).…”

Section: J a Bosch Et Alsupporting

confidence: 77%

Salivary MUC5B-Mediated Adherence (Ex Vivo) of Helicobacter pylori During Acute Stress

Bosch

Geus

Ligtenberg

et al. 2000

Psychosomatic Medicine

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Objective: Biochemical host defenses at mucosal sites, such as the oral cavity, play a key role in the regulation of microbial ecology and the prevention of infectious disease. These biochemical factors have distinct features, some of which benefit the host and some that benefit bacteria. We investigated the effects of acute stress on the salivary levels of the carbohydrate structure sulfo-Lewis a (sulfo-Le a ), which is linked to the mucosal glycoprotein MUC5B. Sulfo-Le a was recently identified as an adhesion molecule for Helicobacter pylori; therefore, we also measured saliva-mediated adherence (ex vivo) of H. pylori. The oral cavity is suspected to be involved in the transmission of H. pylori. Methods: Saliva was collected from 17 undergraduates before (baseline), during (stress), and after (recovery) exposure to a video showing surgical procedures. In addition, blood pressure, an impedance cardiogram, and an electrocardiogram were recorded. Results: During stressor exposure, participants reported increased state anxiety. In addition, stroke volume increased and heart rate decreased. The stressor induced a strong increase in salivary sulfo-Le a concentration (U/ml), sulfo-Le a output (U/min), sulfo-Le a /total protein ratio (U/mg protein), and saliva-mediated adherence (ex vivo) of H. pylori. As expected, sulfo-Le a concentration correlated with the adherence of H. pylori (r ϭ 0.72, p Ͻ .05). It was demonstrated that the observed adherence was induced by MUC5B and that the carbohydrate structure sulfo-Le a contributed to this process. Conclusions: Our study demonstrated a direct link between stress-mediated biochemical changes and altered host-microbe interactions in humans. Increased bacterial adherence may be a contributing factor in the observed relationship between stress and susceptibility to infectious disease.

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Section: J a Bosch Et Alsupporting

confidence: 77%

Salivary MUC5B-Mediated Adherence (Ex Vivo) of Helicobacter pylori During Acute Stress

Bosch

Geus

Ligtenberg

et al. 2000

Psychosomatic Medicine

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“…NTR1-mRNA and NT binding sites have been identified in the brain (15), small and large intestine of animals and humans (13,15), human colonic epithelial cell lines (16,17), human blood mononuclear cells (11), and endothelial cells (18). Recently, we demonstrated the presence of NTR1 mRNA in the rat colonic mucosa, including colonic epithelial cells (19). We also showed that administration of the specific NT receptor nonpeptide antagonist SR-48,692 to rats attenuated colonic mucin secretion and mast cell activation following immobilization stress, indicating a critical role for NT in stress-related colonic responses (19).…”

Section: Introductionmentioning

confidence: 99%

Neurotensin is a proinflammatory neuropeptide in colonic inflammation

Castagliuolo¹,

Wang²,

Valenick³

et al. 1999

J. Clin. Invest.

130

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A growing body of evidence suggests that interaction of epithelial and immune cells via neuropeptides, hormones, and cytokines participate in the pathophysiology of diarrhea and intestinal inflammation (reviewed in ref. 1). Neurotensin (NT), a bioactive peptide (2) with a primary distribution in the brain and the gastrointestinal tract, has been localized by immunohistochemistry to endocrine cells (N cells) and neurons in the intestinal mucosa, submucosa, and muscularis of animals and humans (3). A wide range of biological activities has been described for NT with actions on the cardiovascular, gastrointestinal, reproductive, and central nervous systems (3). The known intestinal effects of this peptide include trophic effects on small and large bowel, pancreas, and stomach; inhibition of small bowel and gastric motility; and stimulation of colonic motor activity (3). Studies in animals (3, 4, 5) and humans (3, 6) also demonstrate that NT may modulate fluid secretion in the intestinal tract and that its secretory effects in the ileum may be mediated through a nervous reflex in the enteric nervous system (5).Several lines of evidence indicate that NT may also participate in inflammatory reactions. Intravenous administration of NT to rats causes mast cell degranulation (7) and increases vascular permeability and levels of histamine and leukotriene C4 in the plasma (8); these effects can be inhibited by a specific NT receptor antagonist (9).NT also interacts in vitro with immune and inflammatory cells, including leukocytes (10), peritoneal mast cells (7), and macrophages (11,12). Although these studies point to a role for NT in inflammatory reactions, the possibility that this peptide participates in the pathogenesis of colonic inflammation has not been examined.NT exerts its effects by interacting with specific receptors (NTR) on cell surfaces. Two specific receptors for NT (NTR1 and NTR2), which belong to the seven transmembrane G protein-linked superfamily, have been identified and cloned (13,14). NTR1-mRNA and NT binding sites have been identified in the brain (15), small and large intestine of animals and humans (13, 15), human colonic epithelial cell lines (16,17), human blood mononuclear cells (11), and endothelial cells (18). Recently, we demonstrated the presence of NTR1 mRNA in the rat colonic mucosa, including colonic epithelial cells (19). We also showed that administration of the specific NT receptor nonpeptide antagonist SR-48,692 to rats attenuated colonic mucin secretion and mast cell activation following immobilization stress, indicating a critical role for NT in stress-related colonic responses (19).Clostridium difficile is the primary pathogenic factor of antibiotic-associated diarrhea in humans and animals 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 col...

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“…Several studies underline the importance of NTR1 in several intestinal pathologic conditions. For example, administration of the specific NTR1 antagonist SR 48692 to rats inhibits colonic mucin and prostaglandin E2 secretion and mast cell activation in response to immobilization stress (18). NTR1 antagonism also reduces colonic secretion and inflammation mediated by Clostridium difficile toxin A (19), and increased NTR1 expression is evident in the colonic mucosa during the course of acute colitis mediated by this potent enterotoxin (19).…”

mentioning

confidence: 99%

Metalloproteinase-dependent Transforming Growth Factor-α Release Mediates Neurotensin-stimulated MAP Kinase Activation in Human Colonic Epithelial Cells

Zhao¹,

Zhan²,

Koon³

et al. 2004

Journal of Biological Chemistry

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Expression of the neuropeptide neurotensin (NT) and its high affinity receptor (NTR1) is increased during the course of Clostridium difficile toxin A-induced acute colitis, and NTR1 antagonism attenuates the severity of toxin A-induced inflammation. We recently demonstrated in non-transformed human colonic epithelial NCM460 cells that NT treatment caused activation of a Ras-mediated MAP kinase pathway that significantly contributes to NT-induced interleukin-8 (IL-8) secretion. Here we used NCM460 cells, which normally express low levels of NTR1, and NCM460 cells stably transfected with NTR1 to identify the upstream signaling molecules involved in NT-NTR1-mediated MAP kinase activation. We found that inhibition of the epidermal growth factor receptor (EGFR) by either an EGFR neutralizing antibody or by its specific inhibitor AG1478 (0.2 M) blocked NT-induced MAP kinase activation. Moreover, NT stimulated tyrosine phosphorylation of the EGFR, and pretreatment with a broad spectrum metalloproteinase inhibitor batimastat reduced NT-induced MAP kinase activation. Using neutralizing antibodies against the EGFR ligands EGF, heparin-binding-EGF, transforming growth factor-␣ (TGF␣), or amphiregulin we have shown that only the anti-TGF␣ antibody significantly decreases NT-induced phosphorylation of EGFR and MAP kinases. Furthermore, inhibition of the EGF receptor by AG1478 significantly reduced NT-induced IL-8 promoter activity and IL-8 secretion. This is the first report demonstrating that NT binding to NTR1 transactivates the EGFR and that this response is linked to NT-mediated proinflammatory signaling. Our findings indicate that matrix metalloproteinase-mediated release of TGF␣ and subsequent EGFR transactivation triggers a NT-mediated MAP kinase pathway that leads to IL-8 gene expression in human colonic epithelial cells.Neurotensin (NT), 1 a 13-amino acid neuropeptide originally isolated by Carraway and Leeman (1) from bovine hypothalamus, is also localized in the gastrointestinal tract (2). In the small intestine NT is synthesized and secreted by specific mucosal endocrine cells in response to several different stimuli (3, 4). NT alters motility in the stomach, small bowel, and colon (5-7), stimulates secretion in the ileum (8), pancreas (9), and the biliary tract (10), and causes Cl Ϫ secretion from human colonic mucosa (11). NT also stimulates growth and regeneration of the intestinal mucosa (12, 13) and has been implicated in the pathophysiology of colon cancer (14, 15).Two G protein-coupled receptors (GPCRs) have been described for NT, a high affinity (NTR1) and a low affinity (NTR2) receptor (16). A third, non-G protein-coupled receptor has also been identified (17). Several studies underline the importance of NTR1 in several intestinal pathologic conditions. For example, administration of the specific NTR1 antagonist SR 48692 to rats inhibits colonic mucin and prostaglandin E2 secretion and mast cell activation in response to immobilization stress (18). NTR1 antagonism also reduces colonic secretion and infla...

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A neurotensin antagonist, SR 48692, inhibits colonic responses to immobilization stress in rats.

Cited by 74 publications

References 37 publications

Salivary MUC5B-Mediated Adherence (Ex Vivo) of Helicobacter pylori During Acute Stress

Salivary MUC5B-Mediated Adherence (Ex Vivo) of Helicobacter pylori During Acute Stress

Neurotensin is a proinflammatory neuropeptide in colonic inflammation

Metalloproteinase-dependent Transforming Growth Factor-α Release Mediates Neurotensin-stimulated MAP Kinase Activation in Human Colonic Epithelial Cells

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