Neurotensin is a proinflammatory neuropeptide in colonic inflammation

Abstract

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...

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

“…The highest levels of serum NT we had measured before were present in those children with ASD who had gastrointestinal symptoms (27). NT is also found in the gut (29,73) and increases permeability of the intestinal lumen (74). NT may enter the blood and reach the brain by stimulating perivascular mast cells (75,76), which disrupt both the gut-blood barrier (77,78) and the blood-brain barrier (BBB) (79)(80)(81) (Fig.…”

Protease-Activated Receptor 2, Dipeptidyl Peptidase I, and Proteases Mediate Clostridium difficile Toxin A Enteritis

“…These include other receptors known to participate in TxA-induced enteritis, such as the neurotensin receptor 1 and corticotrophin-releasing hormone receptors 1 and 2, both of which are up-regulated in response to TxA, and the CC chemokine receptor (CCR1). [49][50][51] In summary, our use of overlapping genetic and pharmacologic approaches showed that PAR 2 and its activators are proinflammatory in TxA-induced enteritis. Although each of these approaches by themselves has limitations, considered together our results show that deletion of PAR 2 and the proteases that activate this receptor protect against inflammatory responses to TxA.…”

Melanin-concentrating hormone as a mediator of intestinal inflammation

“…Our previous studies on the role of additional neuropeptides such as substance P, neurotensin, and members of the corticotropinreleasing hormone (CRH) family of peptides in intestinal inflammation demonstrated that receptors for these molecules are expressed in intestinal epithelial cells and their expression is increased during the course of inflammation (30)(31)(32)(33)(34). Hence, to examine epithelial cell expression of MCH and its receptors, we used a laser capture microdissection (LCM) approach to isolate colonic epithelial cells from cryopreserved surgical specimens obtained from patients with IBD and controls (35).…”