Human urocortin II, a new CRF-related peptide, displays  selective CRF<sub>2</sub>-mediated action on gastric transit in rats

Million, Mulugeta; Maillot, C; Saunders, Paul R.; Rivier, Jean; Vale, Wylie; Taché, Yvette

doi:10.1152/ajpgi.00283.2001

Cited by 100 publications

(139 citation statements)

References 35 publications

(59 reference statements)

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“…Studies so far have established that CRHR2 activation results in delayed gastric transit in mice, which is most likely mediated by Ucn and UcnII (2,44). Our findings in the present study revealed that among the Ucns that we examined, only UcnII mRNA expression was increased in the ileum of toxin A-injected mice.…”

Section: Discussionsupporting

confidence: 62%

Corticotropin-Releasing Hormone Receptor 2-Deficient Mice Have Reduced Intestinal Inflammatory Responses

Kokkotou

Torres

Moss

et al. 2006

The Journal of Immunology

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Corticotropin-releasing hormone (CRH) and urocortins (Ucn) bind with various affinities to two G-protein-coupled receptors, CRHR1 and CRHR2, which are expressed in brain and in peripheral tissues, including immune cells. CRHR2-deficient mice display anxiety-like behavior, hypersensitivity to stress, altered feeding behavior and metabolism, and cardiovascular abnormalities. However, the phenotype of these mice in inflammatory responses has not been determined. In the present study we found that compared with wild-type CRHR2-null mice developed substantially reduced intestinal inflammation and had lower intestinal mRNA expression of the potent chemoattractants keratinocyte chemokine and monocyte chemoattractant protein 1 following intraluminal exposure to Clostridium difficile toxin A, a potent enterotoxin that mediates antibiotic-associated diarrhea and colitis in humans. This effect was recapitulated by administration of astressin 2B, a selective CRHR2 antagonist, before toxin A exposure. Moreover, Ab array analysis revealed reduced expression of several inflammatory chemokines, including keratinocyte chemokine and monocyte chemoattractant protein 1 in toxin A-exposed mice pretreated with astressin 2B. Real-time RT-PCR of wild-type mouse intestine showed that only UcnII, but not other Ucn, was significantly up-regulated by ileal administration of toxin A at 4 h compared with buffer exposure. We also found that human colonic epithelial HT-29 cells express CRHR2α mRNA, whereas expression of β and γ spliced variants was minimal. Moreover, treatment of HT-29 cells with UcnII, which binds exclusively to CRHR2, stimulated expression of IL-8 and monocyte chemoattractant protein 1. Taken together, these results provide direct evidence that CRHR2 mediates intestinal inflammatory responses via release of proinflammatory mediators at the colonocyte level.

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Section: Discussionsupporting

confidence: 62%

Corticotropin-Releasing Hormone Receptor 2-Deficient Mice Have Reduced Intestinal Inflammatory Responses

Kokkotou

Torres

Moss

et al. 2006

The Journal of Immunology

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“…Various stressors are known to affect gastrointestinal transit in experimental animals, and the affected site and the effect (increase / decrease) differ according to the kind of stress (25,26). Upper gastrointestinal transit was strongly inhibited by restraint stress, as shown in this study in gerbils and in rats (2), but was not affected by force swimming in hot water in rats (27).…”

Section: Discussionsupporting

confidence: 49%

Novelty Stress Increases Fecal Pellet Output in Mongolian Gerbils: Effects of Several Drugs

Okano¹,

Nagaya²,

Inatomi³

2005

J Pharmacol Sci

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Abstract. Stress-induced colonic functional changes have been investigated mainly under conditions involving physical stress, like in the restraint stress model. In this study, we established a new stress-induced defecation model involving the placement of Mongolian gerbils in a novel environment (novelty stress) and determined the effects of several drugs on novelty stress-induced fecal pellet output. When animals kept in groups were placed individually in small cages, the fecal pellet output markedly increased, although the upper intestinal transit measured by charcoal method was not changed. The concentration of plasma adrenocorticotropic hormone was moderately but significantly increased by the novelty stress. Drugs reportedly effective for stress-induced defecation, like alosetron hydrochloride, atropine sulfate, and trimebutine maleate, inhibited both the novelty stress-induced increase in fecal pellet output and spontaneous defecation. In contrast, TAK-637, a tachykinin NK 1 -receptor antagonist, and diazepam inhibited the novelty stress induced defecation but did not inhibit spontaneous defecation. The present study indicated that novelty stress increases fecal pellet output without affecting the upper intestinal transit; this model may be useful for evaluating the effects of drugs on stress-stimulated colonic motility.

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“…The variability of expression, both in quantity and in cell-type, along the GI tract suggests a manner by which Ucn 2 may have different effects in different GI segments. Based on functional studies of CRF-R2, it may be hypothesized that the localization of Ucn 2 in the neuronal plexuses may function in regulating both GI motility [7], as well as visceral pain [8]. Ucn 2 localized to the epithelium may function in controlling mucosal permeability, as the peripheral CRF signaling pathways have been shown to mediate mucosal permeability [11].…”

Section: Discussionmentioning

confidence: 99%

Urocortin 2 expression in the rat gastrointestinal tract under basal conditions and in chemical colitis

et al. 2007

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It is becoming increasingly evident that the urocortins (Ucns) and their receptors are involved in the initiation and development of inflammation in the gastrointestinal (GI) tract. There has not been a systematic study of the basal expression of Ucns or their receptors in the GI tract. Here, we examined basal expression of Ucn 2 and its high-affinity receptor, CRF-R2 in the rat GI tract. Ucn 2 mRNA was expressed throughout the small and large intestine. Surprisingly, CRF-R2 mRNA expression was detected in only a subset of GI regions that expressed Ucn 2. Immunohistochemical study showed that both Ucn 2 immuno-reactivity (Ucn 2-IR) and CRF-R2-IR were consistently seen in the neurons of the myenteric plexus and the nerve fibers innervating the circular muscle. By and large, Ucn 2-IR was detected in all layers, including the mucosal and the submucosal layers throughout the GI regions. In contrast, CRF-R2-IR was very low or undetectable in the mucosal layers of all regions examined. The role of Ucn 2 and CRF-R2 was then examined in a rat model of chemically-induced colitis. In the early phase of colitis, Ucn 2 mRNA levels peaked, whereas, in striking contrast, CRF-R2 mRNA expression decreased ∼2.5-fold below control levels. At the peptide level, Ucn 2-IR was specifically induced in a large population of immune cells that infiltrated the lamina propria and submucosa of the distal colon, whereas CRFR2-IR was detected in only a small fraction of infiltrated immune cells. CRF-R2-IR was dramatically reduced in the neurons of the myenteric plexus. Thus, we show, for the first time, that in the acute phase of inflammation, Ucn 2 levels are increased whereas expression levels of its only identified receptor, CRF-R2, are decreased. This suggests that Ucn 2 exerts its effects only in part via CRF-R2.

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Human urocortin II, a new CRF-related peptide, displays selective CRF₂-mediated action on gastric transit in rats

Cited by 100 publications

References 35 publications

Corticotropin-Releasing Hormone Receptor 2-Deficient Mice Have Reduced Intestinal Inflammatory Responses

Corticotropin-Releasing Hormone Receptor 2-Deficient Mice Have Reduced Intestinal Inflammatory Responses

Novelty Stress Increases Fecal Pellet Output in Mongolian Gerbils: Effects of Several Drugs

Urocortin 2 expression in the rat gastrointestinal tract under basal conditions and in chemical colitis

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Human urocortin II, a new CRF-related peptide, displays selective CRF2-mediated action on gastric transit in rats

Cited by 100 publications

References 35 publications

Corticotropin-Releasing Hormone Receptor 2-Deficient Mice Have Reduced Intestinal Inflammatory Responses

Corticotropin-Releasing Hormone Receptor 2-Deficient Mice Have Reduced Intestinal Inflammatory Responses

Novelty Stress Increases Fecal Pellet Output in Mongolian Gerbils: Effects of Several Drugs

Urocortin 2 expression in the rat gastrointestinal tract under basal conditions and in chemical colitis

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Human urocortin II, a new CRF-related peptide, displays selective CRF₂-mediated action on gastric transit in rats