Neurokinin-1 (NK-1) receptor is required in Clostridium difficile- induced enteritis.

Castagliuolo, Ignazio; Riegler, Martin; Pasha, Asiya; Nikulásson, Sigfús; Liu, Bao; Gérard, Craig; Gerard, Norma P.; Pothoulakis, Charalabos

doi:10.1172/jci2039

Cited by 167 publications

(138 citation statements)

References 27 publications

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“…Also, it can suppress ongoing NK-1R expression. Several animal models support a physiological role for SP and its receptor in liver and intestinal inflammation (1)(2)(3)(4)(5)(6). In many cases NK-1R functions as an enhancer of Th1 pathways.…”

Section: Discussionmentioning

confidence: 99%

“…In murine schistosomiasis, SP through engagement with NK-1R enhances IFN-␥ secretion from Ag-stimulated T cells influencing granuloma formation and IgG2a expression (2,3). The NK-1R helps mediate the mucosal injury induced by Clostridium difficile toxin (4). Also, treatment with blocking SP antiserum (5) or a NK-1R antagonist (6) protects rats from Trichinella spiralis-induced intestinal inflammation.…”

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confidence: 99%

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Substance P Regulates Th1-Type Colitis in IL-10 Knockout Mice

Weinstock

Blum

Metwali

et al. 2003

The Journal of Immunology

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Substance P (SP) is a proinflammatory molecule that interacts with a neurokinin 1 receptor (NK-1R), which is on T cells and helps control IFN-γ production. IL-10−/− mice given a nonsteroidal anti-inflammatory drug (NSAID) develop Th1 colitis. We studied the importance of SP and NK-1R in this colitis model. LP T cells were isolated to study their NK-1R expression. LP T cells from IL-10−/− mice expressed NK-1R and produced IFN-γ only after NSAID treatment and induction of colitis. LP T cells from NSAID-treated wild-type controls or from age-matched untreated IL-10−/− animals did not express NK-1R or produce IFN-γ. Experiments showed that IL-12 induced NK-1R transcription in CD4+ T cells cultured in vitro. However, T cells cultured with IL-12 and IL-10 did not express NK-1R. IL-10 also down-modulated ongoing NK-1R expression. Mice given NK-1R antagonist after NSAID induction of severe colitis showed nearly complete reversal of inflammation, and LP T cells ceased IFN-γ secretion. Thus, intestinal inflammation in IL-10−/− mice is associated with the appearance of NK-1R in mucosal T cells, and an interplay between IL-12 and IL-10 regulates T cell NK-1R transcription. NK-1R antagonist reverses ongoing intestinal inflammation attesting to the importance of SP and its receptor in mucosal inflammation.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Substance P Regulates Th1-Type Colitis in IL-10 Knockout Mice

Weinstock

Blum

Metwali

et al. 2003

The Journal of Immunology

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“…Before anesthesia and at the end of the experiment, blood samples were taken by retroorbital eye bleeding of conscious mice by using heparinized capillary tubes for plasma corticosterone measure-ments. A laparotomy was then performed, and one 3-to 5-cm-long loop was formed at the terminal ileum as described (34). Loops were injected with either 0.15 ml of 50 mM Tris buffer (pH 7.4) containing 10 g of purified toxin A or buffer alone (control).…”

Section: Methodsmentioning

confidence: 99%

Corticotropin-releasing hormone (CRH) requirement inClostridium difficiletoxin A-mediated intestinal inflammation

Anton

Mykoniatis²,

Pan³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Clostridium difficile, the causative agent of antibiotic-associated colitis, mediates inflammatory diarrhea by releasing toxin A, a potent 308-kDa enterotoxin. Toxin A-induced inflammatory diarrhea involves many steps, including mucosal release of substance P (SP) corticotropin-releasing hormone (CRH) and neutrophil transmigration. Here we demonstrate that, compared with wild type, mice genetically deficient in CRH (Crh ؊/؊ ) have dramatically reduced ileal fluid secretion, epithelial cell damage, and neutrophil transmigration 4 h after intraluminal toxin A administration. This response is associated with diminished mucosal activity of the neutrophil enzyme myeloperoxidase compared with that of wildtype mice. In wild-type mice, toxin A stimulates an increase in intestinal SP content compared with buffer administration. In contrast, toxin A administration in Crh ؊/؊ mice fails to result in an increased SP content. Moreover, immunohistochemical experiments showed that CRH and SP are colocalized in some enteric nerves of wild-type mice, and this colocalization is more evident after toxin A administration. These results provide direct evidence for a major proinflammatory role for CRH in the pathophysiology of enterotoxin-mediated inflammatory diarrhea and indicate a SP-linked pathway.C orticotropin-releasing hormone (CRH), a 41-aa peptide, is a major peptide hormone that modulates the activity of the hypothalamic-pituitary-adrenal axis during stress, including inflammation (1-3). CRH mediates its effects by binding to its G protein-coupled receptor subtypes, CRH1 and CRH2 (4-6). CRH plays a dual role in the pathophysiology of inflammation. CRH secreted from the hypothalamus has indirect antiinflammatory effects via stimulation of glucocorticoid release, but CRH is also expressed peripherally, and its expression is increased in leukocytes, nerve fibers, and other cells involved in inflammatory reactions (7-12). Moreover, in vivo and in vitro studies indicate that CRH is a potent proinflammatory peptide (7,(12)(13)(14)(15).A limited number of studies indicate that CRH and its receptors play a role in the pathophysiology of intestinal inflammation. Thus, Van Tol et al. (11) found increased CRH expression in the rat cecum in colitis induced by injection of peptidoglycan-polysaccharide polymers. Increased expression of CRH-immunoreactive cells was also evident in the colonic mucosa of patients with inflammatory bowel disease (16). CRH gene expression is increased in hypothalamic neurons during colitis after intracolonic administration of 2,4,6-trinitrobenzenesulfonic acid (17) and appears to play a protective role in the worsening of experimental colitis induced by stress (18). We have recently shown that expression of CRH as well as CRH1 and CRH2 was dramatically increased in mouse ileum shortly after intraluminal administration of Clostridium difficile toxin A (19). Moreover, experiments with CRH receptor antagonists indicate that CRH plays a proinflammatory role in toxin A-induced intestinal secretion and inflammatio...

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“…Additional studies are required to define the precise sites of receptor expression in normal and diseased states, and tissue-specific silencing of CRF-R1 and CRF-R2 by RNAi could identify the functionally important receptors. One CRF target could be enteric nerves containing the neuropeptide substance P, an essential mediator of toxin A ileitis (12). CRF and substance P colocalize in ileal nerves, and CRF deletion prevents toxin A-induced up-regulation of substance P (9).…”

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confidence: 99%

The stressed gut: Contributions of intestinal stress peptides to inflammation and motility

Bunnett

2005

Proc. Natl. Acad. Sci. U.S.A.

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Neurokinin-1 (NK-1) receptor is required in Clostridium difficile- induced enteritis.

Cited by 167 publications

References 27 publications

Substance P Regulates Th1-Type Colitis in IL-10 Knockout Mice

Substance P Regulates Th1-Type Colitis in IL-10 Knockout Mice

Corticotropin-releasing hormone (CRH) requirement inClostridium difficiletoxin A-mediated intestinal inflammation

The stressed gut: Contributions of intestinal stress peptides to inflammation and motility

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