Urocortin and corticotropin-releasing factor receptor expression in the human colonic mucosa

Muramatsu, Yasunari; Fukushima, Kouhei; Iino, Kazumi; Totsune, Kazuhito; Takahashi, Kazuhiro; Suzuki, Takashi; Hirasawa, Gen; Takeyama, Junji; Ito, Meiichi; Nose, Masato; Tashiro, Atsushi; Hongo, Michio; Osuga, Yutaka; Nishimura, Hiroshi; Sasano, Hironobu

doi:10.1016/s0196-9781(00)00335-1

Cited by 155 publications

(121 citation statements)

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“…Our current findings (Fig. 5), together with results from previous studies (6,11,16,19), suggest that CRH secreted from neurons of the intestinal mucosa in response to administration of toxin A may stimulate the release of SP and possibly other peptides from enteric nerves and sensory neurons that initiate and perpetuate a cascade of neuroimmunointeractions associated with the acute intestinal inflammatory response. More studies are needed to identify the mechanism of interaction(s) between these two important proinflammatory neuropeptides.…”

Section: Discussionsupporting

confidence: 82%

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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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Section: Discussionsupporting

confidence: 82%

“…CRH mediates its effects by binding to its G protein-coupled receptor subtypes, CRH1 and CRH2 (4)(5)(6). CRH plays a dual role in the pathophysiology of inflammation.…”

mentioning

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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“…The possible leakage of CRF from the brain to the periphery during stress is supported by the demonstration of active CRF transport from the brain to the periphery (22). However, CRF and Ucn are expressed in the GI tract (9,12,16,25) and immune cells (2). There is also preliminary evidence from PCR analysis that high levels of selective CRF 2 ligands are expressed in the stomach (12), supporting the possibility that CRF-related peptides may act through local nonhormonal mechanisms as reported for other peripheral actions of CRF (2,28).…”

Section: Discussionmentioning

confidence: 97%

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

Million

Maillot

Saunders

et al. 2002

American Journal of Physiology-Gastrointestinal and Liver Physi

100

129

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Human urocortin (hUcn) II is a new member of the corticotropin-releasing factor (CRF) family that selectively binds to the CRF2 receptor. We investigated the CRF receptors involved in mediating the effects of hUcn II and human/rat CRF (h/rCRF) on gut transit. Gastric emptying, 4 h after a solid meal, and distal colonic transit (bead expulsion time) were monitored simultaneously in conscious rats. CRF antagonists were given subcutaneously 30 min before intravenous injection of peptides or partial restraint (for 90 min). hUcn II (3 or 10 g/kg iv) inhibited gastric emptying (by 45% and 55%, respectively) and did not influence distal colonic transit. The CRF2 peptide antagonist astressin2-B blocked hUcn II action. h/rCRF, rat Ucn, and restraint delayed gastric emptying while accelerating distal colonic transit. The gastric response to intravenous h/rCRF and restraint was blocked by the CRF2 antagonist but not by the CRF1 antagonist CP-154,526, whereas the colonic response was blocked only by CP-154,526. None of the CRF antagonists influenced postprandial gut transit. These data show that intravenous h/rCRF and restraint stress-induced delayed gastric emptying involve CRF2 whereas stimulation of distal colonic transit involves CRF1. The distinct profile of hUcn II, only on gastric transit, is linked to its CRF2 selectivity. partial restraint; gastric emptying; distal colonic transit; CP-154,526; astressin2-B

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“…The involvement of neurons was suggested by modulation of the CRH response by atropine, hexamethonim, and bretylium (5,28). Peripheral effects of CRH have been shown to regulate colonic motor activity (18), and expression of CRH and CRH receptors is also found in the colonic mucosa of rodents (19) and humans (13,23). Coutinho et al (7) recently reported that maternal separation induced visceral hyperalgesia and increased colonic motility in adult rats.…”

Section: Discussionmentioning

confidence: 99%

Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress

Söderholm¹,

Yates²,

Gareau³

et al. 2002

American Journal of Physiology-Gastrointestinal and Liver Physi

208

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. Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress. Am J Physiol Gastrointest Liver Physiol 283: G1257-G1263, 2002. First published August 28, 2002 10.1152/ajpgi.00314.2002Intestinal dysfunction is related to stress and early life events, but the mechanisms are largely unknown. Our aim was to determine whether early trauma predisposes adult rats to intestinal mucosal dysfunction in response to stress. Neonatal Sprague-Dawley rats were individually separated from their mothers for 3 h/day at 4-21 days of age. Between days 80 and 90, separated and control rats were subjected to mild acute stress (30-min water avoidance) or sham stress. Mucosal barrier function and ion transport were assessed in colonic tissues mounted in Ussing chambers. Mild stress increased short-circuit current, conductance, and transepithelial transport of macromolecules in separated rats, while having minimal effects in controls. Pretreatment of the separated rats with a corticotropin-releasing hormone (CRH) antagonist, the peptide ␣-helical CRH(9-41) injected intraperitoneally 20 min before stress, abolished the stress-induced mucosal changes. Our results indicate that neonatal trauma can induce phenotypic changes in adulthood, including enhanced vulnerability of the gut mucosa to stress via mechanisms involving peripherally located CRH receptors.behavior; corticotropin-releasing hormone; electron microscopy; ion transport; intestinal permeability HUMANS EXPERIENCE STRESS OF various types during daily life, and adequate responses to these stressors are necessary for survival. If the severity or the chronicity of the stressful experience exceeds the adaptive capacity, the individual will be predisposed to illness and disease in multiple organ systems (21). A large number of studies have shown that early-life experience plays an important role in stress responsiveness throughout life (8). In animal models, neonatal adversity can result in permanent functional changes in the stress-mediating systems of the central nervous system (15). For example, newborn rats subjected to maternal separation demonstrate increased release of corticotropinreleasing hormone (CRH), altered expression of glucocorticoid receptors, as well as changes in the norepinephrine and GABA systems (3, 4). Recently, it was also shown in humans that adverse early-life events are associated with hyperresponsiveness to stress and alterations in the hypothalamic-pituitaryadrenal (HPA) axis (10).There is evidence that early-life trauma and ongoing psychological stress can affect the clinical course of intestinal disorders (16,17,20,26) and also reactivate inflammation in experimental colitis (6,9,22,25). The mechanisms underlying stress-induced exacerbations of intestinal diseases are, however, largely unknown. One possible link between intestinal disease and stress is a change in mucosal function. Our previous studies have shown that acute stress in rats induces enhanced intestinal epithelial permeability to macromolecu...

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Urocortin and corticotropin-releasing factor receptor expression in the human colonic mucosa

Cited by 155 publications

References 51 publications

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

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

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

Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress

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Urocortin and corticotropin-releasing factor receptor expression in the human colonic mucosa

Cited by 155 publications

References 51 publications

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

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

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

Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress

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