Human Mast Cells Express Corticotropin-Releasing Hormone (CRH) Receptors and CRH Leads to Selective Secretion of Vascular Endothelial Growth Factor

Cao, Jing; Papadopoulou, Nikoletta; Kempuraj, Duraisamy; Boucher, William; Sugimoto, Kazunori; Cetrulo, Curtis L.; Theoharides, Theoharis C.

doi:10.4049/jimmunol.174.12.7665

Cited by 294 publications

(269 citation statements)

References 67 publications

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“…A combination of local and extrinsic signals may be involved in mediating the effect of CRF on colonic epithelial function. CRF-Rs were also localized in the periphery, with expression on enteric nerves (5,18), crypt epithelial cells (5), and mast cells (4). The effects of CRF to modify colonic epithelial physiology may occur either directly on the colonic epithelium or indirectly by activating cholinergic nerves to release acetylcholine.…”

Section: Discussionmentioning

confidence: 99%

Neonatal maternal separation of rat pups results in abnormal cholinergic regulation of epithelial permeability

Gareau

Jury

Perdue

2007

American Journal of Physiology-Gastrointestinal and Liver Physi

125

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Gareau MG, Jury J, Perdue MH. Neonatal maternal separation of rat pups results in abnormal cholinergic regulation of epithelial permeability. Am J Physiol Gastrointest Liver Physiol 293: G198-G203, 2007. First published May 17, 2007; doi:10.1152/ajpgi.00392.2006.-Neonatal maternal separation (MS) predisposes adult rats to develop stressinduced mucosal barrier dysfunction/visceral hypersensitivity and rat pups to develop colonic epithelial dysfunction. Our aim was to examine if enhanced epithelial permeability in such pups resulted from abnormal regulation by enteric nerves. Pups were separated from the dam for 3 h/day (days 4 -20); nonseparated (NS) pups served as controls. On day 20, colonic tissues were removed and mounted in Ussing chambers. Horseradish peroxidase (HRP) flux was used to measure macromolecular permeability. HRP flux was increased in MS versus NS pups. The enhanced flux was inhibited by the cholinergic muscarinic antagonist atropine and the nicotinic antagonist hexamethonium. The cholinergic component was greater in tissues from MS versus NS pups, suggesting that increased cholinergic activity was responsible for the MS elevated permeability. Western blots and immunohistochemistry of colonic tissues demonstrated increased expression of choline acetyltransferase (ChAT) in MS pups, indicating greater synthesis of acetylcholine. Since a previous study indicated that corticotrophin-releasing factor (CRF) mediates barrier dysfunction in MS pups, we examined if the two pathways were linked. In MS tissues, nonselective CRF receptor antagonism inhibited the enhanced flux, and the addition of atropine did not produce further inhibition. Using selective receptor antagonists, we identified that CRF receptor 2 was involved in mediating this effect. These findings suggest that CRF, via CRF receptor 2, acts on cholinergic nerves to induce epithelial barrier dysfunction. Our study provides evidence that MS stimulates synthesis of acetylcholine, which, together with released CRF, creates a condition conducive to the development of epithelial barrier defects. stress; colonic; barrier THE NEONATAL PERIOD is an important developmental period in humans and rodents, and stress during this time can have long-lasting effects on behavior and physiology. Maternal separation (MS) is a well-characterized model of early life stress used in the study of anxiety and depression (17, 31) as well as intestinal dysfunction (1,2,7,28,37). The physiological response to stress is controlled by the hypothalamicpituitary adrenal (HPA) axis, which develops during the neonatal period. Exposure to stress during this time results in the formation of a dysregulated axis with a compromised ability to downregulate the synthesis of corticotrophin-releasing factor (CRF), a key stress hormone (26).Adult rats of a stress susceptible strain that are subjected to daily separation from the dam during the neonatal period demonstrate increased colonic permeability (2) and visceral hyperalgesia (28). Adult rats that are not genetically susceptible t...

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Section: Discussionmentioning

confidence: 99%

Neonatal maternal separation of rat pups results in abnormal cholinergic regulation of epithelial permeability

Gareau

Jury

Perdue

2007

American Journal of Physiology-Gastrointestinal and Liver Physi

125

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“…Th is process involves selective release of mediators, as shown for serotonin, eicosanoids, interleukin-6, or vascular endothelial growth factor ( 13 ). It is of particular signifi cance that CRH secreted in the gut under stress induces mast cell release of vascular endothelial growth factor ( 14 ), which is also vasodilatory and pro-infl ammatory. Th is process has to be taken into account in any evaluation of mast cell function in diseased states, because it does not require increased mast cell numbers and no degranulation making it nearly impossible to discern any signifi cant diff erences at the light microscope level.…”

Section: Guarantorsmentioning

confidence: 99%

“…A critical role of mast cells in infl ammatory conditions and eff ects of stress have been well documented ( 15 -17 ). In fact, mast cells can be directly activated by CRH through high-affi nity receptors ( 14 ). Again, no conclusions can be made about relationships between mast cell levels and abnormal acute stress responses.…”

Section: Guarantorsmentioning

confidence: 99%

Editorial: Irritable Bowel Syndrome and the Elusive Mast Cells

Theoharides¹,

Asadi²,

Chen³

et al. 2012

American Journal of Gastroenterology

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Irritable bowel syndrome (IBS) is the most common condition seen by gastroenterologists. It presents with alternating symptoms of bowel dysfunction that often worsens with stress. The cause of these symptoms eludes investigators and many attempts have been made to discover an underlying pathology. This is a daunting task since symptoms come and go, and change characteristics. Furthermore, the pathology of IBS is unlikely to be identical in all patients. In addition, all symptoms and all features studied thus far have a strong overlap with healthy volunteers. Elsewhere in this issue, Braak et al. report a well-designed clinical investigation in patients with IBS and come to the conclusion that IBS is not characterized by mast cell or other immune cell proliferation, but by immune dysregulation in the colon. Is this the fi nal answer? Am J Gastroenterol 2012; 107:727 -729; doi: 10.1038/ajg.2012 Irritable bowel syndrome (IBS) is a common functional disorder in the West ( 1 ) and in Asia ( 2 ), which is characterized clinically as abdominal discomfort or pain with alternating constipation and diarrhea. Mechanistic pathways to symptom generation are unclear, although dysfunction of brain-gut communication, gut motility, visceral perception, neuroimmune responses, infl ammation, and mucosal integrity, as well as the psychosocial status might be involved ( 3 ). Th e mucosa contains endings of the enteric sensory nerves; these aff erent nerves can modify motility and pain perception. Th erefore, immune cell infi ltration assessed in mucosal biopsies may provide critical information on the mechanisms of symptom generation. Both intestinal ( 4 ) and colonic ( 5,6 ) biopsies have been investigated. Mast cells have received particular attention because its secretory products, such as histamine, prostaglandins, and proteinases, are capable of sensorimotor dysfunction. IBS appears to worsen with stress and the important information might be obtained from relationships between stress, corticotropin-releasing hormone (CRH) and symptoms ( 7 ). CRH signaling pathways have been shown to have an important role in stress-related alterations of gut function related to intestinal symptoms ( 7 ). Braak et al. ( 8 ) have attempted to clarify IBS pathophysiology using these strategies.Mast cells are well known to modulate gastrointestinal pathophysiology and are considered to be involved in IBS ( 9 ). Increased numbers of mast cells have been reported in the terminal ileum in patients with IBS, although there was lack of correlation with diarrhea-predominant IBS symptoms ( 4 ). Braak et al. ( 8 ) conclude that the number of mast cells, macrophages (CD68), T cells (CD3 and CD8), and λ FLC-positive mast cells is decreased in IBS patients compared with healthy volunteers. As a general statement, this needs clarifi cation. Th ey note the decrease in the descending colon, but no change was seen in the ascending colon and immune cell numbers in the small intestine were not measured. Furthermore, mast cells in the gut musculature ( ...

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“…This response appears to be mediated, at least in part, by adenylate cyclase and cAMP. 21 The authors postulate that this mechanism may be implicated in the stress-induced worsening of arthritis or psoriasis. Together with these observations, the findings of Yang and colleagues 5 now question whether this pathway may also be involved in stress-induced worsening of chronic inflammatory disorders of the gut, including food allergy.…”

mentioning

confidence: 99%

“…20 A recent report has now provided the first evidence that mast cells express CRH receptors. 21 On binding to CRH, mast cells secrete vascular endothelial growth factor (VEGF), but not tryptase, histamine or any of its typical pro-inflammatory cytokines. This response appears to be mediated, at least in part, by adenylate cyclase and cAMP.…”

mentioning

confidence: 99%

How Stress Induces Intestinal Hypersensitivity

Buret

2006

The American Journal of Pathology

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Human Mast Cells Express Corticotropin-Releasing Hormone (CRH) Receptors and CRH Leads to Selective Secretion of Vascular Endothelial Growth Factor

Cited by 294 publications

References 67 publications

Neonatal maternal separation of rat pups results in abnormal cholinergic regulation of epithelial permeability

Neonatal maternal separation of rat pups results in abnormal cholinergic regulation of epithelial permeability

Editorial: Irritable Bowel Syndrome and the Elusive Mast Cells

How Stress Induces Intestinal Hypersensitivity

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