Corticotropin-releasing hormone antagonists possess anti-inflammatory effects in the mouse ileum

Wlk, Michael; Wang, Chi C.; Venihaki, Maria; Liu, Jennifer; Zhao, Dan; Anton, Pauline M.; Mykoniatis, Andreas; Pan, Amy; Zacks, Jeff; Karalis, Katia; Pothoulakis, Charalabos

doi:10.1053/gast.2002.34783

Cited by 75 publications

(95 citation statements)

References 41 publications

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“…Thus, a local stressor, toxin A, induces the synthesis and release of CRF by enteric neurons, which acts within the gut itself to cause inflammation. The results are in line with reports that CRF antagonism and deletion prevent toxin Ainduced ileitis (8,9). However, in those studies it was not possible to determine whether CRF from the central or enteric sources was involved.…”

supporting

confidence: 90%

“…How does CRF exert its proinflammatory and antipropulsive effects? CRF-Rs are expressed by enteric neurons and epithelial cells and in the lamina propria (11), and the levels are up-regulated in the inflamed intestine (8). 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.…”

mentioning

confidence: 99%

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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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supporting

confidence: 90%

mentioning

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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“…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.…”

Section: Contributions Of Proteases To C Difficile Txa-induced Enteritismentioning

confidence: 86%

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

et al. 2007

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“…52,53 It is noteworthy that CRHR1 has a key role in inflammation, 54,55 and that CRHR1 antagonists, which have been used to treat depression, 34,35 also suppress peripheral inflammation. [56][57][58] Antidepressants are known to modulate inflammatory responses after chronic administration, in a time course that is reminiscent of the time frame of antidepressant effects and they also confer protection against cytokine-induced depressive-like biological and behavioral changes. 50,51,[59][60][61] Moreover, concentrations of circulating immune mediators have been found to be elevated in depression.…”

Section: Discussionmentioning

confidence: 99%

Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans

et al. 2004

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There are well-replicated, independent lines of evidence supporting a role for corticotropinreleasing hormone (CRH) in the pathophysiology of depression. CRH receptor 1 (CRHR1), which we first mapped in the brain in 1994, has been implicated in the treatment of depression and anxiety. We studied the association of CRHR1 genotypes with the phenotype of antidepressant treatment response in 80 depressed Mexican-Americans in Los Angeles who completed a prospective randomized, placebo lead-in, double-blind treatment of fluoxetine or desipramine, with active treatment for 8 weeks. Subjects were included into the study if they had a diagnosis of depression without other confounding medical or psychiatric diagnoses or treatments. All patients were followed weekly and assessed for changes in the Hamilton rating scales for anxiety (HAM-A) and depression (HAM-D). Inclusion criteria in the study included a HAM-D of 18 or higher. Because CRHR1 affects both depression and anxiety. Patients were classified into a high-anxiety (HA) group if their HAM-A score was 18 or higher and in a low-anxiety (LA) group if their HAM-A score was less than 18. Utilizing the haplotype-tag single-nucleotide polymorphisms rs1876828, rs242939 and rs242941, we tested for haplotypic association between CRHR1 and 8-week response to daily antidepressant treatment. In the HA group (n ¼ 54), homozygosity for the GAG haplotype was associated with a relative 70% greater reduction in HAM-A scores compared to heterozygous (63.174.5 vs 37.176.9%, respectively, P ¼ 0.002). For HAM-D, GAG haplotype homozygosity was associated with a 31% greater reduction in scores after treatment compared to heterozygous (67.374.3 vs 51.276.0%, respectively, P ¼ 0.03). In those with loweranxiety levels at screening, there were no associations between CRHR1 genotype and percent change in HAM-A or HAM-D. These findings of increased response to antidepressants in highly anxious patients homozygous for the GAG haplotype of CRHR1 need to be independently validated and replicated. Such work would support the hypotheses that response to antidepressant treatment is heterogeneous and that the CRHR1 gene and possibly other genes in stress-inflammatory pathways are involved in response to antidepressant treatment. These findings also suggest that variations in the CRHR1 gene may affect response to CRHR1 agonists or antagonists. All data are deposited in www.pharmgkb. Keywords: corticotropin-releasing hormone; corticotropin-releasing hormone receptor; MexicanAmerican; Hispanic; depression; anxiety Major depression is a common and complex disorder of gene-environment interactions. 1 The specific genetic substrates and precipitating environmental factors have not yet been elucidated. The disorder affects 10% of males and 20% of females and has a point prevalence of 3%. Its cost to the US economy exceeds 100 billion dollars per year. 2 Over 20 drugs are approved by the US Food and Drug Administration for treatment of depression, each one with efficacy of approximately 60%. Various subgroups ...

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Corticotropin-releasing hormone antagonists possess anti-inflammatory effects in the mouse ileum

Cited by 75 publications

References 41 publications

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

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

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

Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans

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