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Liu L, Jin YD, Fan YH. Progress in research of corticotropin-releasing hormone receptor 2 in inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2024; 32:742-749. [DOI: 10.11569/wcjd.v32.i10.742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/26/2024] [Accepted: 10/21/2024] [Indexed: 10/28/2024] Open
Abstract
Members of the corticotropin-releasing hormone family and their receptors are widely distributed in central and peripheral tissues and are involved in the regulation of the cardiovascular system, metabolism, immune function, and inflammatory response in the body. Corticotropin-releasing hormone receptor 2 (CRHR2), one of specific receptors for corticotropin releasing factor, attenuates stress-induced intestinal hypersensitivity, influences intestinal microbial composition and diversity, has strong anti-inflammatory capacity, and regulates the proliferation, migration, and apoptosis of intestinal epithelial cells, and promotes intestinal mucosal repair. In recent years, studies have shown that the levels of CRHR2 in the colon tissue of patients with inflammatory bowel disease (IBD) are significantly different from those in normal human intestinal tissue, and it has been suggested that CRHR2 may be a potential therapeutic target for IBD. This paper reviews the physiological functions of CRHR2 and its clinical relevance to IBD, with the aim of exploring its specific mechanism of action and potential clinical application in the treatment of IBD, so as to provide a basis for the development of more effective therapeutic means for IBD in the future.
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Affiliation(s)
- Liu Liu
- Department of Gastroen-terology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310000, Zhejiang Province, China
| | - Yi-Dan Jin
- Department of Gastroen-terology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310000, Zhejiang Province, China
| | - Yi-Hong Fan
- Department of Gastroen-terology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310000, Zhejiang Province, China
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Zhu C, Li S. Role of CRH in colitis and colitis-associated cancer: a combinative result of central and peripheral effects? Front Endocrinol (Lausanne) 2024; 15:1363748. [PMID: 38616821 PMCID: PMC11010637 DOI: 10.3389/fendo.2024.1363748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 03/19/2024] [Indexed: 04/16/2024] Open
Abstract
Corticotropin-releasing factor family peptides (CRF peptides) comprise corticotropin releasing hormone (CRH), urocortin (UCN1), UCN2 and UCN3. CRH is first isolated in the brain and later with UCNs found in many peripheral cells/tissues including the colon. CRH and UCNs function via the two types of receptors, CRF1 and CRF2, with CRH mainly acting on CRF1, UCN1 on both CRF1 &CRF2 and UCN2-3 on CRF2. Compiling evidence shows that CRH participates in inflammation and cancers via both indirect central effects related to stress response and direct peripheral influence. CRH, as a stress-response mediator, plays a significant central role in promoting the development of colitis involving colon motility, immunity and gut flora, while a few anti-colitis results of central CRH are also reported. Moreover, CRH is found to directly influence the motility and immune/inflammatory cells in the colon. Likewise, CRH is believed to be greatly related to tumorigenesis of many kinds of cancers including colon cancer via the central action during chronic stress while the peripheral effects on colitis-associated-colon cancer (CAC) are also proved. We and others observe that CRH/CRF1 plays a significant peripheral role in the development of colitis and CAC in that CRF1 deficiency dramatically suppresses the colon inflammation and CAC. However, up to date, there still exist not many relevant experimental data on this topic, and there seems to be no absolute clearcut between the central and direct peripheral effects of CRH in colitis and colon cancer. Taken together, CRH, as a critical factor in stress and immunity, may participate in colitis and CAC as a centrally active molecule; meanwhile, CRH has direct peripheral effects regulating the development of colitis and CAC, both of which will be summarized in this review.
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Affiliation(s)
| | - Shengnan Li
- Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
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Khajavi A, Radvar M, Moeintaghavi A. Socioeconomic determinants of periodontitis. Periodontol 2000 2022; 90:13-44. [PMID: 35950737 DOI: 10.1111/prd.12448] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Amin Khajavi
- Craniomaxillofacial Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrdad Radvar
- Department of Periodontology, Mashhad Dental School, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Moeintaghavi
- Department of Periodontology, Mashhad University of Medical Sciences, Mashhad, Iran
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Psychological Stress Exacerbates Inflammation of the Ileum via the Corticotropin-Releasing Hormone-Mast Cell Axis in a Mouse Model of Eosinophilic Enteritis. Int J Mol Sci 2022; 23:ijms23158538. [PMID: 35955675 PMCID: PMC9369025 DOI: 10.3390/ijms23158538] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 07/26/2022] [Accepted: 07/29/2022] [Indexed: 12/10/2022] Open
Abstract
The effects of psychological stress on eosinophilic gastrointestinal disorders have not been elucidated. This study investigated the effects of psychological stress in a mouse model of eosinophilic enteritis (EoN). BALB/c mice were treated with ovalbumin (OVA) to create an EoN model and subjected to either water avoidance stress (WAS) or sham stress (SS). Microscopic inflammation, eosinophil and mast cell counts, mRNA expression, and protein levels of type 2 helper T cell (Th2) cytokines in the ileum were compared between groups. We evaluated ex vivo intestinal permeability using an Ussing chamber. A corticotropin-releasing hormone type 1 receptor (CRH-R1) antagonist was administered before WAS, and its effects were analyzed. WAS significantly increased diarrhea occurrence and, eosinophil and mast cell counts, and decreased the villus/crypt ratio compared to those in the SS group. The mRNA expression of CRH, interleukin IL-4, IL-5, IL-13, eotaxin-1, and mast cell tryptase β2 significantly increased, and the protein levels of IL-5, IL-13, and OVA-specific immunoglobulin E (IgE) also significantly increased in the WAS group. Moreover, WAS significantly increased the intestinal permeability. The CRH-R1 antagonist significantly inhibited all changes induced by WAS. Psychological stress exacerbated ileal inflammation via the CRH-mast cell axis in an EoN mouse model.
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Bruce JK, Burns GL, Sinn Soh W, Nair PM, Sherwin S, Fan K, Dowling LR, Goggins BJ, Koloski N, Potter M, Bollipo S, Foster R, Gan LT, Veysey M, Philpott DJ, Girardin SE, Holtmann G, Kaiko GE, Walker MM, Talley NJ, Keely S. Defects in NLRP6, autophagy and goblet cell homeostasis are associated with reduced duodenal CRH receptor 2 expression in patients with functional dyspepsia. Brain Behav Immun 2022; 101:335-345. [PMID: 35093492 DOI: 10.1016/j.bbi.2022.01.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 12/09/2021] [Accepted: 01/21/2022] [Indexed: 02/07/2023] Open
Abstract
Functional dyspepsia (FD) affects up to 15% of the population and is characterised by recurring upper gastrointestinal (GI) symptoms occurring in the absence of clinically identifiable pathology. Psychological stress is a key factor associated with the onset of FD and locally acting hypothalamic-pituitary-adrenal (HPA) axis hormones have been implicated in GI motility and barrier dysfunction. Recent pre-clinical work has identified mechanistic pathways linking corticotropin-releasing hormone (CRH) with the innate epithelial immune protein NLRP6, an inflammasome that has been shown to regulate GI mucus secretion. We recruited twelve FD patients and twelve healthy individuals to examine whether dysregulation of hypothalamic-pituitary adrenal (HPA) axis hormones and altered NLRP6 pathways were evident in the duodenal mucosa. Protein expression was assessed by immunoblot and immunohistochemistry in D2 duodenal biopsies. Plasma HPA axis hormones were assayed by ELISA and enteroid and colorectal cancer cell line cultures were used to verify function. FD patients exhibited reduced duodenal CRH-receptor 2, compared to non-GI disease controls, indicating a dysregulation of duodenal HPA signalling. The loss of CRH-receptor 2 correlated with reduced NLRP6 expression and autophagy function, processes critical for maintaining goblet cell homeostasis. In accordance, duodenal goblet cell numbers and mucin exocytosis was reduced in FD patients compared to controls. In vitro studies demonstrated that CRH could reduce NLRP6 in duodenal spheroids and promote mucus secretion in the HT29-MTX-E12 cell line. In conclusion, FD patients exhibit defects in the NLRP6-autophagy axis with decreased goblet cell function that may drive symptoms of disease. These features correlated with loss of CRH receptor 2 and may be driven by dysregulation of HPA signalling in the duodenum of FD patients.
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Affiliation(s)
- Jessica K Bruce
- School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia; Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Grace L Burns
- School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Wai Sinn Soh
- School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Prema M Nair
- School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Simonne Sherwin
- School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - KeNing Fan
- School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Laura R Dowling
- School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Bridie J Goggins
- School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Natasha Koloski
- School of Medicine & Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; Department of Gastroenterology, John Hunter Hospital, Newcastle, New South Wales, Australia; Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, and Faculty of Medicine, The University of Queensland, Woolloongabba, Queensland, Australia
| | - Michael Potter
- NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia; School of Medicine & Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia
| | - Steven Bollipo
- Department of Gastroenterology, John Hunter Hospital, Newcastle, New South Wales, Australia
| | - Robert Foster
- Department of Gastroenterology, John Hunter Hospital, Newcastle, New South Wales, Australia
| | - Lay T Gan
- Department of Gastroenterology, John Hunter Hospital, Newcastle, New South Wales, Australia
| | - Martin Veysey
- NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia; School of Medicine & Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia
| | - Dana J Philpott
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Stephen E Girardin
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Gerald Holtmann
- NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, and Faculty of Medicine, The University of Queensland, Woolloongabba, Queensland, Australia
| | - Gerard E Kaiko
- School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Marjorie M Walker
- NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia; School of Medicine & Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia
| | - Nicholas J Talley
- NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia; School of Medicine & Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia
| | - Simon Keely
- School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; NHMRC Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.
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Zhao SB, Wu JY, He ZX, Song YH, Chang X, Xia T, Fang X, Li ZS, Xu C, Wang SL, Bai Y. Corticotropin releasing hormone promotes inflammatory bowel disease via inducing intestinal macrophage autophagy. Cell Death Dis 2021; 7:377. [PMID: 34873177 PMCID: PMC8648763 DOI: 10.1038/s41420-021-00767-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 11/07/2021] [Accepted: 11/15/2021] [Indexed: 12/16/2022]
Abstract
Psychosocial stress is a vital factor contributing to the pathogenesis and progression of inflammatory bowel disease (IBD). The contribution of intestinal macrophage autophagy to the onset and development of IBD has been widely studied. Herein, we investigated the underlying mechanism of psychosocial stress in an IBD mouse model pertaining to macrophage autophagy. Corticotropin releasing hormone (CRH) was peripherally administrated to induce psychosocial stress. For in vivo studies, dextran sulfate sodium (DSS) was used for the creation of our IBD mouse model. For in vitro studies, lipopolysaccharide (LPS) was applied on murine bone marrow-derived macrophages (BMDMs) as a cellular IBD-related challenge. Chloroquine was applied to inhibit autophagy. We found that CRH aggravated the severity of DSS-induced IBD, increasing overall and local inflammatory reactions and infiltration. The levels of autophagy in intestinal macrophages and murine BMDMs were increased under these IBD-related inflammatory challenges and CRH further enhanced these effects. Subsequent administration of chloroquine markedly attenuated the detrimental effects of CRH on IBD severity and inflammatory reactions via inhibition of autophagy. These findings illustrate the effects of peripheral administration of CRH on DSS-induced IBD via the enhancement of intestinal macrophage autophagy, thus providing a novel understanding as well as therapeutic target for the treatment of IBD.
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Affiliation(s)
- Sheng-Bing Zhao
- grid.73113.370000 0004 0369 1660Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China
| | - Jia-Yi Wu
- grid.73113.370000 0004 0369 1660Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China
| | - Zi-Xuan He
- grid.73113.370000 0004 0369 1660Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China
| | - Yi-Hang Song
- grid.73113.370000 0004 0369 1660Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China
| | - Xin Chang
- grid.73113.370000 0004 0369 1660Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China ,grid.417279.eDepartment of Gastroenterology, General Hospital of Central Theater Command, Wuhan, China
| | - Tian Xia
- grid.73113.370000 0004 0369 1660Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China
| | - Xue Fang
- grid.73113.370000 0004 0369 1660Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China
| | - Zhao-Shen Li
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China.
| | - Can Xu
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China.
| | - Shu-Ling Wang
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China.
| | - Yu Bai
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China.
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Stress and Nasal Allergy: Corticotropin-Releasing Hormone Stimulates Mast Cell Degranulation and Proliferation in Human Nasal Mucosa. Int J Mol Sci 2021; 22:ijms22052773. [PMID: 33803422 PMCID: PMC7967145 DOI: 10.3390/ijms22052773] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 02/27/2021] [Accepted: 03/06/2021] [Indexed: 12/12/2022] Open
Abstract
Psychological stress exacerbates mast cell (MC)-dependent inflammation, including nasal allergy, but the underlying mechanisms are not thoroughly understood. Because the key stress-mediating neurohormone, corticotropin-releasing hormone (CRH), induces human skin MC degranulation, we hypothesized that CRH may be a key player in stress-aggravated nasal allergy. In the current study, we probed this hypothesis in human nasal mucosa MCs (hM-MCs) in situ using nasal polyp organ culture and tested whether CRH is required for murine M-MC activation by perceived stress in vivo. CRH stimulation significantly increased the number of hM-MCs, stimulated both their degranulation and proliferation ex vivo, and increased stem cell factor (SCF) expression in human nasal mucosa epithelium. CRH also sensitized hM-MCs to further CRH stimulation and promoted a pro-inflammatory hM-MC phenotype. The CRH-induced increase in hM-MCs was mitigated by co-administration of CRH receptor type 1 (CRH-R1)-specific antagonist antalarmin, CRH-R1 small interfering RNA (siRNA), or SCF-neutralizing antibody. In vivo, restraint stress significantly increased the number and degranulation of murine M-MCs compared with sham-stressed mice. This effect was mitigated by intranasal antalarmin. Our data suggest that CRH is a major activator of hM-MC in nasal mucosa, in part via promoting SCF production, and that CRH-R1 antagonists such as antalarmin are promising candidate therapeutics for nasal mucosa neuroinflammation induced by perceived stress.
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Extra-adrenal glucocorticoid biosynthesis: implications for autoimmune and inflammatory disorders. Genes Immun 2020; 21:150-168. [PMID: 32203088 PMCID: PMC7276297 DOI: 10.1038/s41435-020-0096-6] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 03/05/2020] [Accepted: 03/09/2020] [Indexed: 12/11/2022]
Abstract
Glucocorticoid synthesis is a complex, multistep process that starts with cholesterol being delivered to the inner membrane of mitochondria by StAR and StAR-related proteins. Here its side chain is cleaved by CYP11A1 producing pregnenolone. Pregnenolone is converted to cortisol by the enzymes 3-βHSD, CYP17A1, CYP21A2 and CYP11B1. Glucocorticoids play a critical role in the regulation of the immune system and exert their action through the glucocorticoid receptor (GR). Although corticosteroids are primarily produced in the adrenal gland, they can also be produced in a number of extra-adrenal tissue including the immune system, skin, brain, and intestine. Glucocorticoid production is regulated by ACTH, CRH, and cytokines such as IL-1, IL-6 and TNFα. The bioavailability of cortisol is also dependent on its interconversion to cortisone which is inactive, by 11βHSD1/2. Local and systemic glucocorticoid biosynthesis can be stimulated by ultraviolet B, explaining its immunosuppressive activity. In this review, we want to emphasize that dysregulation of extra-adrenal glucocorticoid production can play a key role in a variety of autoimmune diseases including multiple sclerosis (MS), lupus erythematosus (LE), rheumatoid arthritis (RA), and skin inflammatory disorders such as psoriasis and atopic dermatitis (AD). Further research on local glucocorticoid production and its bioavailability may open doors into new therapies for autoimmune diseases.
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Baritaki S, de Bree E, Chatzaki E, Pothoulakis C. Chronic Stress, Inflammation, and Colon Cancer: A CRH System-Driven Molecular Crosstalk. J Clin Med 2019; 8:E1669. [PMID: 31614860 PMCID: PMC6833069 DOI: 10.3390/jcm8101669] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 10/08/2019] [Accepted: 10/11/2019] [Indexed: 12/12/2022] Open
Abstract
Chronic stress is thought to be involved in the occurrence and progression of multiple diseases, via mechanisms that still remain largely unknown. Interestingly, key regulators of the stress response, such as members of the corticotropin-releasing-hormone (CRH) family of neuropeptides and receptors, are now known to be implicated in the regulation of chronic inflammation, one of the predisposing factors for oncogenesis and disease progression. However, an interrelationship between stress, inflammation, and malignancy, at least at the molecular level, still remains unclear. Here, we attempt to summarize the current knowledge that supports the inseparable link between chronic stress, inflammation, and colorectal cancer (CRC), by modulation of a cascade of molecular signaling pathways, which are under the regulation of CRH-family members expressed in the brain and periphery. The understanding of the molecular basis of the link among these processes may provide a step forward towards personalized medicine in terms of CRC diagnosis, prognosis and therapeutic targeting.
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Affiliation(s)
- Stavroula Baritaki
- Division of Surgery, School of Medicine, University of Crete, Heraklion, 71500 Crete, Greece.
| | - Eelco de Bree
- Division of Surgery, School of Medicine, University of Crete, Heraklion, 71500 Crete, Greece.
| | - Ekaterini Chatzaki
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
| | - Charalabos Pothoulakis
- IBD Center, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 10833, USA.
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Chatoo M, Li Y, Ma Z, Coote J, Du J, Chen X. Involvement of Corticotropin-Releasing Factor and Receptors in Immune Cells in Irritable Bowel Syndrome. Front Endocrinol (Lausanne) 2018; 9:21. [PMID: 29483895 PMCID: PMC5816029 DOI: 10.3389/fendo.2018.00021] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 01/18/2018] [Indexed: 12/12/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder defined by ROME IV criteria as pain in the lower abdominal region, which is associated with altered bowel habit or defecation. The underlying mechanism of IBS is not completely understood. IBS seems to be a product of interactions between various factors with genetics, dietary/intestinal microbiota, low-grade inflammation, and stress playing a key role in the pathogenesis of this disease. The crosstalk between the immune system and stress in IBS mechanism is increasingly recognized. Corticotropin-releasing factor (CRF), a major mediator in the stress response, is involved in altered function in GI, including inflammatory processes, colonic transit time, contractile activity, defecation pattern, pain threshold, mucosal secretory function, and barrier functions. This mini review focuses on the recently establish local GI-CRF system, its involvement in modulating the immune response in IBS, and summarizes current IBS animal models and mapping of CRF, CRFR1, and CRFR2 expression in colon tissues. CRF and receptors might be a key molecule involving the immune and movement function via brain-gut axis in IBS.
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Affiliation(s)
- Mahanand Chatoo
- Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yi Li
- Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhiqiang Ma
- Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
| | - John Coote
- School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom
| | - Jizeng Du
- Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Medical Neurobiology of the Ministry of Health, Institute of Neuroscience, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Medical Neurobiology of Zhejiang Province, Institute of Neuroscience, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xuequn Chen
- Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Medical Neurobiology of the Ministry of Health, Institute of Neuroscience, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Medical Neurobiology of Zhejiang Province, Institute of Neuroscience, School of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Xuequn Chen,
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11
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Zhang M, Sun K, Wu Y, Yang Y, Tso P, Wu Z. Interactions between Intestinal Microbiota and Host Immune Response in Inflammatory Bowel Disease. Front Immunol 2017; 8:942. [PMID: 28855901 PMCID: PMC5558048 DOI: 10.3389/fimmu.2017.00942] [Citation(s) in RCA: 236] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 07/24/2017] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract. Although the etiology and pathogenesis of IBD remain unclear, both genetic susceptibility and environmental factors are implicated in the initiation and progression of IBD. Recent studies with experimental animal models and clinical patients indicated that the intestinal microbiota is one of the critical environmental factors that influence nutrient metabolism, immune responses, and the health of the host in various intestinal diseases, including ulcerative colitis and Crohn’s disease. The objective of this review is to highlight the crosstalk between gut microbiota and host immune response and the contribution of this interaction to the pathogenesis of IBD. In addition, potential therapeutic strategies targeting the intestinal micro-ecosystem in IBD are discussed.
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Affiliation(s)
- Ming Zhang
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, Beijing, China
| | - Kaiji Sun
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, Beijing, China
| | - Yujun Wu
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, Beijing, China
| | - Ying Yang
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, Beijing, China
| | - Patrick Tso
- Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, United States
| | - Zhenlong Wu
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing, China
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Fang X, Hong Y, Dai L, Qian Y, Zhu C, Wu B, Li S. CRH promotes human colon cancer cell proliferation via IL-6/JAK2/STAT3 signaling pathway and VEGF-induced tumor angiogenesis. Mol Carcinog 2017; 56:2434-2445. [PMID: 28618089 DOI: 10.1002/mc.22691] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 06/01/2017] [Accepted: 06/13/2017] [Indexed: 12/14/2022]
Abstract
Corticotrophin-releasing hormone (CRH) has been demonstrated to participate in various diseases. Our previous study showed that its receptor CRHR1 mediated the development of colitis-associated cancer in mouse model. However, the detailed mechanisms remain unclear. In this study, we explored the oncogenetic role of CRH/CRHR1 signaling in colon cancer cells. Cell proliferation and colony formation assays revealed that CRH contributed to cell proliferation. Moreover, tube formation assay showed that CRH-treated colon cancer cell supernatant significantly promoted tube formation of human umbilical vein endothelial cells (HUVECs). And these effects could be reversed by the CRHR1 specific antagonist Antalarmin. Further investigation showed that CRH significantly upregulated the expressions of interlukin-6 (IL-6) and vascular endothelial growth factor (VEGF) through activating nuclear factor-kappa B (NF-κB). The CRH-induced IL-6 promoted phosphorylation of janus kinase 2 (JAK2) and signal transducers and activators of transcription 3 (STAT3). STAT3 inhibition by Stattic significantly inhibited the CRH-induced cell proliferation. In addition, silence of VEGF resulted in declined tube formation induced by CRH. Taken together, CRH/CRHR1 signaling promoted human colon cancer cell proliferation via NF-κB/IL-6/JAK2/STAT3 signaling pathway and tumor angiogenesis via NF-κB/VEGF signaling pathway. Our results provide evidence to support a critical role for the CRH/CRHR1 signaling in colon cancer progression and suggest its potential utility as a new therapeutic target for colon cancer.
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Affiliation(s)
- Xianjun Fang
- Department of Pharmacology, Nanjing Medical University, Nanjing, China
| | - Yali Hong
- Department of Pharmacology, Nanjing Medical University, Nanjing, China
| | - Li Dai
- Department of Pharmacology, Nanjing Medical University, Nanjing, China
| | - Yuanyuan Qian
- Department of Pharmacology, Nanjing Medical University, Nanjing, China
| | - Chao Zhu
- Department of Pharmacology, Nanjing Medical University, Nanjing, China
| | - Biao Wu
- Department of Surgery, The first affiliated hospital, Nanchang University, Nanchang, China
| | - Shengnan Li
- Department of Pharmacology, Nanjing Medical University, Nanjing, China
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13
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Hussain Z, Kim HW, Huh CW, Lee YJ, Park H. The Effect of Peripheral CRF Peptide and Water Avoidance Stress on Colonic and Gastric Transit in Guinea Pigs. Yonsei Med J 2017; 58:872-877. [PMID: 28541004 PMCID: PMC5447122 DOI: 10.3349/ymj.2017.58.4.872] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 04/15/2017] [Accepted: 04/18/2017] [Indexed: 12/19/2022] Open
Abstract
Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are common gastrointestinal (GI) diseases; however, there is frequent overlap between FD and IBS patients. Emerging evidence links the activation of corticotropin releasing factor (CRF) receptors with stress-related alterations of gastric and colonic motor function. Therefore, we investigated the effect of peripheral CRF peptide and water avoidance stress (WAS) on upper and lower GI transit in guinea pigs. Dosages 1, 3, and 10 μg/kg of CRF were injected intraperitoneally (IP) in fasted guinea pigs 30 minutes prior to the intragastric administration of charcoal mix to measure upper GI transit. Colonic transits in non-fasted guinea pigs were assessed by fecal pellet output assay after above IP CRF doses. Blockade of CRF receptors by Astressin, and its effect on GI transit was also analyzed. Guinea pigs were subjected to WAS to measure gastrocolonic transit in different sets of experiments. Dose 10 μg/kg of CRF significantly inhibited upper GI transit. In contrast, there was dose dependent acceleration of the colonic transit. Remarkably, pretreatment of astressin significantly reverses the effect of CRF peptide on GI transit. WAS significantly increase colonic transit, but failed to accelerate upper GI transit. Peripheral CRF peptide significantly suppressed upper GI transit and accelerated colon transit, while central CRF involved WAS stimulated only colonic transit. Therefore, peripheral CRF could be utilized to establish the animal model of overlap syndrome.
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Affiliation(s)
- Zahid Hussain
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hae Won Kim
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Cheal Wung Huh
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Young Ju Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hyojin Park
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
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14
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Xu WX. Central and Peripheral Modulation of Visceral Pain and Visceral Hypersensitivity by the CRF-CRFR System. ACTA ACUST UNITED AC 2017. [DOI: 10.15406/ghoa.2017.06.00207] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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15
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Bernardazzi C, Pêgo B, de Souza HSP. Neuroimmunomodulation in the Gut: Focus on Inflammatory Bowel Disease. Mediators Inflamm 2016; 2016:1363818. [PMID: 27471349 PMCID: PMC4947661 DOI: 10.1155/2016/1363818] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 06/07/2016] [Indexed: 12/17/2022] Open
Abstract
Intestinal immunity is finely regulated by several concomitant and overlapping mechanisms, in order to efficiently sense external stimuli and mount an adequate response of either tolerance or defense. In this context, a complex interplay between immune and nonimmune cells is responsible for the maintenance of normal homeostasis. However, in certain conditions, the disruption of such an intricate network may result in intestinal inflammation, including inflammatory bowel disease (IBD). IBD is believed to result from a combination of genetic and environmental factors acting in concert with an inappropriate immune response, which in turn interacts with nonimmune cells, including nervous system components. Currently, evidence shows that the interaction between the immune and the nervous system is bidirectional and plays a critical role in the regulation of intestinal inflammation. Recently, the maintenance of intestinal homeostasis has been shown to be under the reciprocal control of the microbiota by immune mechanisms, whereas intestinal microorganisms can modulate mucosal immunity. Therefore, in addition to presenting the mechanisms underlying the interaction between immune and nervous systems in the gut, here we discuss the role of the microbiota also in the regulation of neuroimmune crosstalk involved in intestinal homeostasis and inflammation, with potential implications to IBD pathogenesis.
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Affiliation(s)
- Claudio Bernardazzi
- Serviço de Gastroenterologia & Laboratório Multidisciplinar de Pesquisa, Hospital Universitário, Universidade Federal do Rio de Janeiro, 21941-913 Rio de Janeiro, RJ, Brazil
| | - Beatriz Pêgo
- Serviço de Gastroenterologia & Laboratório Multidisciplinar de Pesquisa, Hospital Universitário, Universidade Federal do Rio de Janeiro, 21941-913 Rio de Janeiro, RJ, Brazil
| | - Heitor Siffert P. de Souza
- Serviço de Gastroenterologia & Laboratório Multidisciplinar de Pesquisa, Hospital Universitário, Universidade Federal do Rio de Janeiro, 21941-913 Rio de Janeiro, RJ, Brazil
- D'Or Institute for Research and Education (IDOR), 22281-100 Rio de Janeiro, RJ, Brazil
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16
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Identification of a novel interaction between corticotropin releasing hormone (Crh) and macroautophagy. Sci Rep 2016; 6:23342. [PMID: 26987580 PMCID: PMC4796911 DOI: 10.1038/srep23342] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 03/02/2016] [Indexed: 02/07/2023] Open
Abstract
In inflammatory bowel disease (IBD), compromised restitution of the epithelial barrier contributes to disease severity. Owing to the complexity in the pathogenesis of IBD, a variety of factors have been implicated in its progress. In this study, we report a functional interaction between macroautophagy and Corticotropin Releasing Hormone (Crh) in the gut. For this purpose we used DSS colitis model on Crh -/- or wild-type (wt) with pharmacological inhibition of autophagy. We uncovered sustained basal autophagy in the gut of Crh -/- mice, which persisted over the course of DSS administration. Autophagy inhibition resulted in partial rescue of Crh -/- mice, while it increased the expression of Crh in the wt gut. Similarly, Crh deficiency was associated with sustained activation of base line autophagy. In vitro models of amino acid deprivation- and LPS-induced autophagy confirmed the in vivo findings. Our results indicate a novel role for Crh in the intestinal epithelium that involves regulation of autophagy, while suggesting the complementary action of the two pathways. These data suggest the intriguing possibility that targeting Crh stimulation in the intestine may provide a novel therapeutic approach to support the integrity of the epithelial barrier and to protect from chronic colitis.
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18
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Hoffman JM, Baritaki S, Ruiz JJ, Sideri A, Pothoulakis C. Corticotropin-Releasing Hormone Receptor 2 Signaling Promotes Mucosal Repair Responses after Colitis. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 186:134-44. [PMID: 26597886 DOI: 10.1016/j.ajpath.2015.09.013] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 08/10/2015] [Accepted: 09/10/2015] [Indexed: 01/09/2023]
Abstract
The corticotropin-releasing hormone family mediates functional responses in many organs, including the intestine. Activation of corticotropin-releasing hormone receptor 2 (CRHR2) in the colonic mucosa promotes inflammation during acute colitis but inhibits inflammation during chronic colitis. We hypothesized that specific modulation of CRHR2 signaling in the colonic mucosa can promote restoration of the epithelium through stimulation of cell proliferative, migratory, and wound healing responses. Mucosal repair was assessed after dextran sodium sulfate (DSS)-induced colitis in mice receiving intracolonic injections of a CRHR2 antagonist or vehicle and in Crhr2(-/-) mice. Histologic damage, cytokine expression, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, and Ki-67 immunoreactivity were evaluated. Cell viability, proliferation, and migration were compared between parental and CRHR2-overexpressing colonic epithelial cells. Protein lysates were processed for phosphoprotein assays and a wound healing assay performed in vitro. Administration of a CRHR2 antagonist after DSS-induced colitis increased disease activity, delayed healing, and decreased epithelial cell proliferation in vivo. Colons from these mice also showed increased apoptosis and proinflammatory cytokine expression. Compared with controls, Crhr2(-/-) mice showed increased mortality in the DSS healing protocol. CRHR2-overexpressing cells had increased proliferation and migration compared with parental cells. Wound healing and signal transducer and activator of transcription 3 activity were elevated in CRHR2-overexpressing cells after urocortin 2 and IL-6 treatment, suggesting advanced healing progression. Our results suggest that selective CRHR2 activation may provide a targeted approach to enhance mucosal repair pathways after colitis.
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Affiliation(s)
- Jill M Hoffman
- Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Stavroula Baritaki
- Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Jonathan J Ruiz
- Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Aristea Sideri
- Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Charalabos Pothoulakis
- Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
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19
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Im E. Multi-facets of Corticotropin-releasing Factor in Modulating Inflammation and Angiogenesis. J Neurogastroenterol Motil 2015; 21:25-32. [PMID: 25540945 PMCID: PMC4288099 DOI: 10.5056/jnm14076] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Revised: 10/02/2014] [Accepted: 10/04/2014] [Indexed: 12/20/2022] Open
Abstract
The family of corticotropin-releasing factor (CRF) composed of 4 ligands including CRF, urocortin (Ucn) 1, Ucn2, and Ucn3 is expressed both in the central nervous system and the periphery including the gastrointestinal tract. Two different forms of G protein coupled receptors, CRF1 and CRF2, differentially recognize CRF family members, mediating various biological functions. A large body of evidence suggests that the CRF family plays an important role in regulating inflammation and angiogenesis. Of particular interest is a contrasting role of the CRF family during inflammatory processes. The CRF family can exert both pro-and anti-inflammatory functions depending on the type of receptors, the tissues, and the disease phases. In addition, there has been a growing interest in a possible role of the CRF family in angiogenesis. Regulation of angiogenesis by the CRF family has been shown to modulate endogenous blood vessel formation, inflammatory neovascularization and cardiovascular function. This review outlines the effect of the CRF family and its receptors on 2 major biological events: inflammation and angiogenesis, and provides a possibility of their application for the treatment of inflammatory vascular diseases.
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Affiliation(s)
- Eunok Im
- College of Pharmacy, Pusan National University, Busan, Korea
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Liu Y, Fang X, Yuan J, Sun Z, Li C, Li R, Li L, Zhu C, Wan R, Guo R, Jin L, Li S. The role of corticotropin-releasing hormone receptor 1 in the development of colitis-associated cancer in mouse model. Endocr Relat Cancer 2014; 21:639-51. [PMID: 25015995 DOI: 10.1530/erc-14-0239] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Patients with ulcerative colitis are at a very high risk of developing colorectal cancer. Corticotrophin-releasing hormone (CRH) family peptides and their receptors (CRHRs) are found to modulate inflammation and tumor cell growth. However, the role of CRH family peptides and their receptors in the inflammation-related colon cancer is still unknown. The aim of this study was to investigate the functions of CRHR1 signaling on the development of colitis-associated cancer (CAC). Crhr1-deficient (Crhr1(-/-)) mice were used to explore the role of CRHR1 in the development of azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced CAC. WT (Crhr1(+/+)) littermates were set as control. We found that the expression of CRHR1 and its endogenous ligands: urocortin and CRH were enhanced in the colon of Crhr1(+/+) mice during treatment with AOM and DSS. Tumorigenesis was significantly reduced in Crhr1(-/-) mice, determined by analysis of survival rate (increased by 20%), weight loss (decreased by 10%), tumor formation (decreased by 60% in tumor number), histological scores (decreased by 58%), and cytokine production. During early CAC tumorigenesis, Crhr1(-/-) mice exhibited much less tumorigenesis, accompanied by lower inflammatory response, including decreased IL1β, IL6 and TNFα expression and macrophage infiltration and increased IL10 expression. Moreover, Crhr1(-/-) mice displayed a reduced activation of NFκB and STAT3 phosphorylation with decreased proliferating and enhanced apoptotic cells in the colon. In conclusion, CRHR1 has a proinflammatory and therefore a protumorigenesis effect in terms of CAC, which may be helpful to develop new therapeutic approaches for inflammation and cancer prevention and treatment.
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Affiliation(s)
- Yunxin Liu
- Key Laboratory of Cardiovascular and Molecular InterventionDepartment of Pharmacology, Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Xianjun Fang
- Key Laboratory of Cardiovascular and Molecular InterventionDepartment of Pharmacology, Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Jie Yuan
- Key Laboratory of Cardiovascular and Molecular InterventionDepartment of Pharmacology, Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Zongxing Sun
- Key Laboratory of Cardiovascular and Molecular InterventionDepartment of Pharmacology, Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Chuanhua Li
- Key Laboratory of Cardiovascular and Molecular InterventionDepartment of Pharmacology, Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Rong Li
- Key Laboratory of Cardiovascular and Molecular InterventionDepartment of Pharmacology, Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Li Li
- Key Laboratory of Cardiovascular and Molecular InterventionDepartment of Pharmacology, Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Chao Zhu
- Key Laboratory of Cardiovascular and Molecular InterventionDepartment of Pharmacology, Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Rong Wan
- Key Laboratory of Cardiovascular and Molecular InterventionDepartment of Pharmacology, Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Rui Guo
- Key Laboratory of Cardiovascular and Molecular InterventionDepartment of Pharmacology, Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Lai Jin
- Key Laboratory of Cardiovascular and Molecular InterventionDepartment of Pharmacology, Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Shengnan Li
- Key Laboratory of Cardiovascular and Molecular InterventionDepartment of Pharmacology, Nanjing Medical University, Nanjing 210029, People's Republic of China
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21
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Hill LT, Kidson SH, Michell WL. Corticotropin-releasing factor is present in intestinal tissue of patients with gastrointestinal dysfunction following shock and abdominal surgery. Nutrition 2013; 29:650-4. [PMID: 23466050 DOI: 10.1016/j.nut.2012.11.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Revised: 09/07/2012] [Accepted: 11/26/2012] [Indexed: 02/05/2023]
Abstract
OBJECTIVE Corticotropin-releasing factor (CRF) is implicated in stress-related gastrointestinal dysfunction, possibly causing gut dysfunction following trauma and surgery. We investigated plasma and intestinal tissue CRF levels and gut function in patients with traumatic shock or those undergoing elective abdominal surgery. RESEARCH METHODS AND PROCEDURES In a prospective, parallel, observational study in a university hospital surgical intensive care unit (ICU), 8 shocked patients (systolic blood pressure <90 mmHg and/or acidosis and/or urine output <1 mL/kg/hr and/or requiring >2 L of intravenous fluid resuscitation) undergoing small bowel resection during emergency laparotomy following abdominal injury and 17 stable patients undergoing elective hepatobiliary surgery were included if they required postoperative ICU management. Serial plasma and intestinal CRF was measured and postoperative gastric emptying and intestinal permeability were evaluated. RESULTS Plasma CRF was significantly increased in the shocked patients compared with the elective surgery patients at all times. CRF peptide was quantified in intestinal tissue at similar levels in both groups. Intestinal permeability was increased and associated with shock and resuscitation fluid volume. Gastric emptying was retarded and correlated significantly with shock but not with plasma CRF. Delayed gastric emptying in shocked patients was associated with longer ICU stay. CONCLUSIONS The novel finding is the presence of CRF in the small bowel of both elective and emergency gastrointestinal surgery patients with concomitant gastrointestinal dysfunction. Circulating CRF is associated with poor gastric emptying, which prolongs ICU stay, whereas shock significantly impairs gastric emptying and gut permeability.
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Affiliation(s)
- Lauren T Hill
- Department of Human Biology, University of Cape Town, South Africa.
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22
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Stasi C, Bellini M, Costa F, Mumolo MG, Ricchiuti A, Grosso M, Duranti E, Metelli MR, Gambaccini D, Bianchi L, Di Tanna GL, Laffi G, Taddei S, Marchi S. Neuroendocrine markers and psychological features in patients with irritable bowel syndrome. Int J Colorectal Dis 2013; 28:1203-1208. [PMID: 23377858 DOI: 10.1007/s00384-013-1646-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/21/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The key role of the brain-gut axis in the pathophysiology of irritable bowel syndrome (IBS) has been recognized. The aim of this study was to assess the possible association between IBS, neuroendocrine markers, and psychological features. METHODS One hundred and twenty-five consecutive IBS patients and 105 healthy subjects were enrolled. Plasma serotonin, plasma and urinary cortisol, and plasma neuropeptide Y levels were evaluated. All patients were given a questionnaire to assess IBS symptom severity. In 66 patients, a psychodiagnostic assessment was carried out. RESULTS A high incidence of specific psychological features, including state anxiety (69.69 %), trait anxiety (54.54 %), obsessions and compulsions (28.78 %), was observed in IBS patients. A positive correlation between neuropeptide Y and state anxiety (r = 0.287, p = 0.024) and simulation/social ingenuity (r = 0.269, p = 0.039) was found in these patients. In diarrhea-predominant IBS, plasma cortisol was linearly related to plasma serotonin (r = 0.5663, p < 0.001). CONCLUSIONS In IBS patients, a significant correlation was found between specific psychological features and neuroendocrine markers, especially plasma cortisol and neuropeptide Y; in diarrhea-predominant IBS, a correlation between plasma cortisol and serotonin was found, although it needs to be confirmed in more extensive cohorts.
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Affiliation(s)
- Cristina Stasi
- Department of Internal Medicine, University of Florence, Florence, Italy.
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23
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Quintanar JL, Guzmán-Soto I. Hypothalamic neurohormones and immune responses. Front Integr Neurosci 2013; 7:56. [PMID: 23964208 PMCID: PMC3741963 DOI: 10.3389/fnint.2013.00056] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 07/16/2013] [Indexed: 01/19/2023] Open
Abstract
The aim of this review is to provide a comprehensive examination of the current literature describing the neural-immune interactions, with emphasis on the most recent findings of the effects of neurohormones on immune system. Particularly, the role of hypothalamic hormones such as Thyrotropin-releasing hormone (TRH), Corticotropin-releasing hormone (CRH) and Gonadotropin-releasing hormone (GnRH). In the past few years, interest has been raised in extrapituitary actions of these neurohormones due to their receptors have been found in many non-pituitary tissues. Also, the receptors are present in immune cells, suggesting an autocrine or paracrine role within the immune system. In general, these neurohormones have been reported to exert immunomodulatory effects on cell proliferation, immune mediators release and cell function. The implications of these findings in understanding the network of hypothalamic neuropeptides and immune system are discussed.
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Affiliation(s)
- J Luis Quintanar
- Laboratory of Neurophysiology, Department of Physiology and Pharmacology, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes Aguascalientes, México
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24
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Sun Y, Zhang M, Chen CC, Gillilland M, Sun X, El-Zaatari M, Huffnagle GB, Young VB, Zhang J, Hong SC, Chang YM, Gumucio DL, Owyang C, Kao JY. Stress-induced corticotropin-releasing hormone-mediated NLRP6 inflammasome inhibition and transmissible enteritis in mice. Gastroenterology 2013; 144:1478-87, 1487.e1-8. [PMID: 23470617 PMCID: PMC3777426 DOI: 10.1053/j.gastro.2013.02.038] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2012] [Revised: 02/23/2013] [Accepted: 02/27/2013] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Stress alters brain-gut interactions and could exacerbate intestinal disorders, including irritable bowel syndrome. Alterations in the intestinal microbiota have been associated with irritable bowel syndrome. Maintenance of healthy microbiota requires nucleotide-binding oligomerization domain protein-like receptors, pyrin-domain containing (NLRP)-6 inflammasomes. We investigated the involvement of NLRP6 in water-avoidance stress (WAS)-induced intestinal disorders in mice. METHODS B57BL6 mice were subjected to WAS for 1 hour each day for 10 days; body weights and intestinal inflammation and permeability were analyzed. We investigated signaling via the NLRP3 and NLRP6 inflammasomes, and the role of corticotropin-releasing hormone (CRH) in WAS-associated inflammation and NLRP6 inhibition. Mice that were not exposed to stress were co-housed with mice subjected to WAS to determine the effects of WAS-induced dysbiosis, measured by sequencing bacterial 16S ribosomal RNA. We also assessed the effects of a peroxisome proliferator-activated receptor-γ agonist and probiotics. RESULTS WAS-induced small-bowel inflammation (enteritis) was associated with inhibition of NLRP6, but not NLRP3, and was prevented by a peroxisome proliferator-activated receptor-γ agonist, which induced epithelial expression of NLRP6. CRH was released during WAS and inhibited NLRP6 expression. WAS induced alterations in the gut microbiota of mice; co-housed nonstressed mice developed enteritis associated with increased CRH and decreased levels of NLRP6. Probiotic therapy reduced intestinal inflammation in mice with WAS-induced enteritis. CONCLUSIONS Exposure of mice to stress inhibits NLRP6 and alters the composition of the gut microbiota, leading to intestinal inflammation. These findings might explain the benefits of probiotics for patients with stress-associated gastrointestinal disorders.
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Affiliation(s)
- Yundong Sun
- Department of Microbiology, Shandong University School of Medicine, Jinan, Shandong, China
- Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Min Zhang
- Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Chun-Chia Chen
- Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital and National, Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Merritt Gillilland
- Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Xia Sun
- Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan
- Institue of Pharmacology, Shandong University School of Medicine, Jinan, Shandong, China
| | - Mohamad El-Zaatari
- Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Gary B. Huffnagle
- Division of Pulmonary and Critical Care, University of Michigan Medical School, Ann Arbor, Michigan
| | - Vincent B. Young
- Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Jiajie Zhang
- Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan
- Zhengzhou Maternal and Child Health Hospital, Zhengzhou, China
| | - Soon-Cheol Hong
- Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Yu-Ming Chang
- Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Deborah L. Gumucio
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Chung Owyang
- Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan
| | - John Y. Kao
- Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan
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25
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Chatzaki E, Anton PA, Million M, Lambropoulou M, Constantinidis T, Kolios G, Taché Y, Grigoriadis DE. Corticotropin-releasing factor receptor subtype 2 in human colonic mucosa: Down-regulation in ulcerative colitis. World J Gastroenterol 2013; 19:1416-1423. [PMID: 23539366 PMCID: PMC3602501 DOI: 10.3748/wjg.v19.i9.1416] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Revised: 12/05/2012] [Accepted: 12/20/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess corticotropin-releasing factor receptor 2 (CRF2) expression in the colon of healthy subjects and patients with ulcerative colitis (UC).
METHODS: We examined CRF2 gene and protein expression in the distal/sigmoid colonic mucosal biopsies from healthy subjects and patients with UC (active or disease in remission), human immunodeficiency virus (HIV) and functional bowel disease (FBD) by reverse transcription-polymerase chain reaction and immunofluorescence.
RESULTS: Gene expression of CRF2 was demonstrated in the normal human colonic biopsies, but not in the human colorectal adenocarcinoma cell line Caco2. Receptor protein localization showed immunoreactive CRF2 receptors in the lamina propria and in the epithelial cells of the distal/sigmoid biopsy samples. Interestingly, CRF2 immunoreactivity was no longer observed in epithelial cells of patients with mild-moderately active UC and disease in remission, while receptor protein expression did not change in the lamina propria. No differences in CRF2 expression profile were observed in distal/sigmoid intestinal biopsies from HIV infection and FBD patients, showing no signs of inflammation.
CONCLUSION: The down-regulation of the CRF2 receptor in the distal/sigmoid biopsies of UC patients is indicative of change in CRF2 signalling associated with the process of inflammation.
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Qi W, Tian J, Zhang C, He J, Ning Z, Jiao P, Liao M. Potential role of HPA axis and sympathetic nervous responses in depletion of B cells induced by H9N2 avian influenza virus infection. PLoS One 2012; 7:e51029. [PMID: 23251416 PMCID: PMC3519482 DOI: 10.1371/journal.pone.0051029] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2012] [Accepted: 10/26/2012] [Indexed: 11/18/2022] Open
Abstract
Except severe pulmonary disease caused by influenza virus infection, an impaired immune system is also a clinic characteristic. However, the mechanism(s) of influenza virus infection-induced depletion of B cells was unknown. Here, we compared the effect of two variant virulence H9N2 virus infections on mouse B cells. Our study found that the infection with highly pathogenic virus (V) of led to depletion of spleen B cells and bone marrow (BM) early B cells, compared to lowly pathogenic virus (Ts). Moreover, high apoptosis and cell cycle arrest in spleen and BM were detected, suggesting important factors for the reduction of B cells in both organs. Further, this effect was not caused by virus replication in spleen and BM. Compared to Ts virus infection, V virus resulted in higher glucocorticoids (GCs) and lower leptin level in plasma. Intraperitoneal GCs receptor antagonist RU486 injection was sufficient to prevent the loss of spleen B cell and BM pro- and immature B cells, but similar result was not observed in leptin-treated mice. Depletion of spleen B cells and BM pro-B cells was also reversed by chemical sympathectomy mediated by the norepinephrine (NE) analog 6-hydroxydopamine (6-OHDA), but the treatment didn't affect the GCs level. This study demonstrated that depletion of B cells induced by H9N2 AIV was dependent on HPA axis and sympathetic response.
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Affiliation(s)
- Wenbao Qi
- College of Veterinary Medicine, South China Agricultural University, Guangdong, People's Republic of China
- MOA Key Laboratory for Animal Vaccine Development, Guangzhou, People's Republic of China
- Key Lab of Zoonoses Control and Prevention of Guangdong, Guangdong, People's Republic of China
| | - Jin Tian
- College of Veterinary Medicine, South China Agricultural University, Guangdong, People's Republic of China
- MOA Key Laboratory for Animal Vaccine Development, Guangzhou, People's Republic of China
- Key Lab of Zoonoses Control and Prevention of Guangdong, Guangdong, People's Republic of China
| | - Changhui Zhang
- College of Veterinary Medicine, South China Agricultural University, Guangdong, People's Republic of China
- MOA Key Laboratory for Animal Vaccine Development, Guangzhou, People's Republic of China
- Key Lab of Zoonoses Control and Prevention of Guangdong, Guangdong, People's Republic of China
| | - Jun He
- College of Veterinary Medicine, South China Agricultural University, Guangdong, People's Republic of China
- MOA Key Laboratory for Animal Vaccine Development, Guangzhou, People's Republic of China
- Key Lab of Zoonoses Control and Prevention of Guangdong, Guangdong, People's Republic of China
| | - Zhangyong Ning
- College of Veterinary Medicine, South China Agricultural University, Guangdong, People's Republic of China
- MOA Key Laboratory for Animal Vaccine Development, Guangzhou, People's Republic of China
- Key Lab of Zoonoses Control and Prevention of Guangdong, Guangdong, People's Republic of China
| | - Peirong Jiao
- College of Veterinary Medicine, South China Agricultural University, Guangdong, People's Republic of China
- MOA Key Laboratory for Animal Vaccine Development, Guangzhou, People's Republic of China
- Key Lab of Zoonoses Control and Prevention of Guangdong, Guangdong, People's Republic of China
| | - Ming Liao
- College of Veterinary Medicine, South China Agricultural University, Guangdong, People's Republic of China
- MOA Key Laboratory for Animal Vaccine Development, Guangzhou, People's Republic of China
- Key Lab of Zoonoses Control and Prevention of Guangdong, Guangdong, People's Republic of China
- * E-mail:
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Yuan PQ, Wu SV, Elliott J, Anton PA, Chatzaki E, Million M, Taché Y. Expression of corticotropin releasing factor receptor type 1 (CRF1) in the human gastrointestinal tract and upregulation in the colonic mucosa in patients with ulcerative colitis. Peptides 2012; 38:62-9. [PMID: 22948128 PMCID: PMC3652978 DOI: 10.1016/j.peptides.2012.07.028] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2012] [Revised: 07/31/2012] [Accepted: 07/31/2012] [Indexed: 12/13/2022]
Abstract
Brain corticotropin-releasing factor (CRF) acting on CRF receptor type 1 (CRF(1)) is a main signaling pathway in the stress response. CRF is also produced in a variety of peripheral sites and acts locally as a proinflammatory mediator. We investigated CRF(1) mRNA expression in the human gastrointestinal tract, and localized CRF(1) immunoreactive cells in the colonic mucosa of healthy subjects and patients with ulcerative colitis (UC). In 4 male healthy subjects (24-29 years), CRF(1) transcript was detected by RT-PCR throughout the gastrointestinal tract with the highest levels in the ileum and rectum and the lowest level in the colon. Immunohistochemistry on whole thickness sigmoid colon sections showed that CRF(1) was localized in the lamina propria and epithelial cells and enteric neurons. In sigmoid colonic biopsies, immunohistochemically double-labeled cells with CRF(1) and CD163, a marker for macrophages, represent 79% of total CRF(1) immunoreactive (IR) cells in healthy subjects. In 10 UC patients, the total number of CRF(1) IR cells and CRF(1)/CD163 double-labeled macrophages was increased by 4.2 and 4.0 folds respectively compared to healthy subjects. These findings indicate that CRF(1) is distributed throughout the GI tract of healthy human subjects. The increase of CRF(1) IR cells prominently in macrophages of the sigmoid colonic mucosa of UC patients provides anatomical support for a role of CRF(1) signaling in modulating the immune-inflammatory process of UC.
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Affiliation(s)
- Pu-Qing Yuan
- CURE: Digestive Diseases Research Center and Center for Neurobiology of Stress, Digestive Diseases Division, Department of Medicine, University of California, Los Angeles, CA 90073, USA.
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The Role of Helicobacter pylori in Upper Respiratory System Infections: Is it More Than Colonization? Curr Infect Dis Rep 2012; 14:128-36. [PMID: 22311663 DOI: 10.1007/s11908-012-0237-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Helicobacter pylori (HP) is recognized as a common chronic human bacterial infection and is the most common cause of gastritis. Recent studies suggest an increased HP prevalence in patients with various extra-digestive inflammatory diseases. Since many respiratory diseases are characterized by chronic inflammation as well as increased immune response, and HP may enter the nasopharyngeal cavity by gastroesophageal reflux, an association between respiratory disorders and HP infection has been suggested. Several studies discover HP in clinical samples from the patients with upper respiratory system infections. Even some of them revealed a relief after the treatment directed to HP eradication. However some studies do not support this theory and whether this association means a definite proof of a causal relationship between HP and respiratory diseases needs to be clarified. In this study, we aimed to review the reports about the role of HP in upper respiratory system infections.
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Yang L, Zheng PY, Liu ZQ. Activation of TLR4 by CRF in human intestinal epithelial cells is mediated by the CRF2 receptor. Shijie Huaren Xiaohua Zazhi 2012; 20:1763-1767. [DOI: 10.11569/wcjd.v20.i19.1763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of corticotrophin-releasing factor (CRF) on the expression of toll-like receptor 4 (TLR4) in human intestinal epithelial cell line HT-29.
METHODS: HT-29 cells were divided into eight groups: non-treated group, LPS group (treated with 20 μg/L LPS for 24 h), CRF group (treated with 20 μg/L CRF for 24 h), LPS plus CRF group (pretreated with 20 μg/L CRF for 12 h and then treated with 20 μg/L LPS for 12 h), astressin 2B plus CRF group (pretreated with 20 μg/L astressin 2B for 12 h and then treated with 20 μg/L CRF), antalarmin plus CRF group (pretreated with 20 μg/L antalarmin for 12 h and then treated with 20 μg/L CRF), astressin 2B plus LPS group (pretreated with 20 μg/L astressin 2B for 12 h and then treated with 20 μg/L LPS), and antalarmin plus LPS group (pretreated with 20 μg/L antalarmin for 12 h and then treated with 20 μg/L LPS). The expression of TLR4 mRNA and protein was detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, respectively. The secretion of interleukin-8 in the culture supernatants was determined by enzyme-linked immunosorbent assay (ELISA).
RESULTS: CRF could induce the expression of TLR4 in HT-29 cells and result in increased interleukin-8 secretion (P < 0.05). CRFR2 antagonist astressin 2B inhibited the expression of LR4 (P < 0.05, CRF+LPS group vs CRF group), while CRF1 antagonist antalarmin had no significant effect on the expression of TLR4 (P > 0.05, CRF+LPS group vs CRF group).
CONCLUSION: The induction of TLR4 expression by CRF in human intestinal epithelial cells is mediated by the CRF2 receptor.
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Chang L, Adeyemo M, Karagiannides I, Videlock EJ, Bowe C, Shih W, Presson AP, Yuan PQ, Cortina G, Gong H, Singh S, Licudine A, Mayer M, Tache Y, Pothoulakis C, Mayer EA, Mayer EA. Serum and colonic mucosal immune markers in irritable bowel syndrome. Am J Gastroenterol 2012; 107:262-72. [PMID: 22158028 PMCID: PMC3297737 DOI: 10.1038/ajg.2011.423] [Citation(s) in RCA: 121] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Low-grade colonic mucosal inflammation has been postulated to have an important role in the pathophysiology of irritable bowel syndrome (IBS). The objectives of this study were (i) to identify serum and tissue-based immunological and neuroendocrine markers associated with mucosal inflammation in male (M) and female (F) patients with non-post-infectious IBS (non-PI-IBS) compared with healthy controls and (ii) to assess possible correlations of such markers with IBS symptoms. METHODS Sigmoid mucosal biopsies were obtained from 45 Rome II positive IBS patients without a history of PI-IBS (26 F, 35.5% IBS-C, 33.3% IBS-D, 31.1% IBS-A/M) and 41 healthy controls (22 F) in order to measure immunological markers (serum cytokine levels, colonic mucosal mRNA levels of cytokines, mucosal immune cell counts) and neuroendocrine markers associated with mucosal inflammation (corticotropin releasing factor- and neurokinin (NK)-related ligands and receptors, enterochromaffin cells). Symptoms were measured using validated questionnaires. RESULTS Of all the serum and mucosal cytokines measured, only interleukin-10 (IL-10) mRNA expression showed a group difference, with female, but not male, patients showing lower levels compared with female controls (18.0±2.9 vs. 29.5±4.0, P=0.006). Mucosal mRNA expression of NK-1 receptor was significantly lower (1.15±0.19 vs. 2.66±0.56, P=0.008) in female, but not male, patients compared with healthy controls. No other significant differences were observed. CONCLUSIONS Immune cell counts and levels of cytokines and neuropeptides that are associated with inflammation were not significantly elevated in the colonic mucosa of non-PI-IBS patients, and did not correlate with symptoms. Thus, these findings do not support that colonic mucosal inflammation consistently has a primary role in these patients. However, the finding of decreased IL-10 mRNA expression may be a possible biomarker of IBS and warrants further investigation.
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Affiliation(s)
- Lin Chang
- Center for Neurobiology of Stress, University of California, Los Angeles, California, USA,Department of Medicine, University of California, Los Angeles, California, USA
| | - Mopelola Adeyemo
- Center for Neurobiology of Stress, University of California, Los Angeles, California, USA,Department of Medicine, University of California, Los Angeles, California, USA
| | - Iordanis Karagiannides
- Department of Medicine, University of California, Los Angeles, California, USA,Inflammatory Bowel Disease Center, Department of Medicine, University of California, Los Angeles, California, USA
| | - Elizabeth J. Videlock
- Center for Neurobiology of Stress, University of California, Los Angeles, California, USA,Department of Medicine, University of California, Los Angeles, California, USA
| | - Collin Bowe
- Department of Medicine, University of California, Los Angeles, California, USA,Inflammatory Bowel Disease Center, Department of Medicine, University of California, Los Angeles, California, USA
| | - Wendy Shih
- Department of Biostatistics, University of California, Los Angeles, California, USA
| | - Angela P. Presson
- Department of Biostatistics, University of California, Los Angeles, California, USA
| | - Pu-Qing Yuan
- Center for Neurobiology of Stress, University of California, Los Angeles, California, USA,Inflammatory Bowel Disease Center, Department of Medicine, University of California, Los Angeles, California, USA,VA GLA Healthcare System, Los Angeles, California, USA
| | - Galen Cortina
- Department of Pathology, University of California, Los Angeles, California, USA
| | - Hua Gong
- Prometheus Laboratories, San Diego, California, USA
| | - Sharat Singh
- Prometheus Laboratories, San Diego, California, USA
| | - Arlene Licudine
- Center for Neurobiology of Stress, University of California, Los Angeles, California, USA,Department of Medicine, University of California, Los Angeles, California, USA
| | - Minou Mayer
- Center for Neurobiology of Stress, University of California, Los Angeles, California, USA,Department of Medicine, University of California, Los Angeles, California, USA
| | - Yvette Tache
- Center for Neurobiology of Stress, University of California, Los Angeles, California, USA,Inflammatory Bowel Disease Center, Department of Medicine, University of California, Los Angeles, California, USA,VA GLA Healthcare System, Los Angeles, California, USA
| | - Charalabos Pothoulakis
- Department of Medicine, University of California, Los Angeles, California, USA,Inflammatory Bowel Disease Center, Department of Medicine, University of California, Los Angeles, California, USA
| | - Emeran A. Mayer
- Center for Neurobiology of Stress, University of California, Los Angeles, California, USA,Department of Medicine, University of California, Los Angeles, California, USA,Department of Physiology, University of California, Los Angeles, California, USA,Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, California, USA,Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, California, USA
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31
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Wallon C, Persborn M, Jönsson M, Wang A, Phan V, Lampinen M, Vicario M, Santos J, Sherman PM, Carlson M, Ericson AC, McKay DM, Söderholm JD. Eosinophils express muscarinic receptors and corticotropin-releasing factor to disrupt the mucosal barrier in ulcerative colitis. Gastroenterology 2011; 140:1597-607. [PMID: 21277851 DOI: 10.1053/j.gastro.2011.01.042] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2010] [Revised: 12/23/2010] [Accepted: 01/13/2011] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Altered intestinal barrier function has been implicated in the pathophysiology of ulcerative colitis (UC) in genetic, functional, and epidemiological studies. Mast cells and corticotropin-releasing factor (CRF) regulate the mucosal barrier in human colon. Because eosinophils are often increased in colon tissues of patients with UC, we assessed interactions among mast cells, CRF, and eosinophils in the mucosal barrier of these patients. METHODS Transmucosal fluxes of protein antigens (horseradish peroxidase) and paracellular markers ((51)Cr-EDTA, fluorescein isothiocyanate-dextran 4000) were studied in noninflamed, colonic mucosal biopsy samples collected from 26 patients with UC and 53 healthy volunteers (controls); samples were mounted in Ussing chambers. We also performed fluorescence and electron microscopy of human tissue samples, assessed isolated eosinophils, and performed mechanistic studies using in vitro cocultured eosinophils (15HL-60), mast cells (HMC-1), and a colonic epithelial cell line (T84). RESULTS Colon tissues from patients with UC had significant increases in permeability to protein antigens compared with controls. Permeability was blocked by atropine (a muscarinic receptor antagonist), α-helical CRF(9-41) (a CRF receptor antagonist), and lodoxamide (a mast-cell stabilizer). Eosinophils were increased in number in UC tissues (compared with controls), expressed the most M2 and M3 muscarinic receptors of any mucosal cell type, and had immunoreactivity to CRF. In coculture studies, carbachol activation of eosinophils caused production of CRF and activation of mast cells, which increased permeability of T84 epithelial cells to macromolecules. CONCLUSIONS We identified a neuroimmune intercellular circuit (from cholinergic nerves, via eosinophils to mast cells) that mediates colonic mucosal barrier dysfunction in patients with UC. This circuit might exacerbate mucosal inflammation.
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Affiliation(s)
- Conny Wallon
- Department of Clinical and Experimental Medicine, Division of Surgery, Linköping University, Sweden
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Buckinx R, Adriaensen D, Nassauw LV, Timmermans JP. Corticotrophin-releasing factor, related peptides, and receptors in the normal and inflamed gastrointestinal tract. Front Neurosci 2011; 5:54. [PMID: 21541251 PMCID: PMC3082851 DOI: 10.3389/fnins.2011.00054] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2011] [Accepted: 04/01/2011] [Indexed: 12/13/2022] Open
Abstract
Corticotrophin-releasing factor (CRF) is mainly known for its role in the stress response in the hypothalamic–pituitary–adrenal axis. However, increasing evidence has revealed that CRF receptor signaling has additional peripheral effects. For instance, activation of CRF receptors in the gastrointestinal tract influences intestinal permeability and motility. These receptors, CRF1 and CRF2, do not only bind CRF, but are also activated by urocortins. Most interestingly, CRF-related signaling also assumes an important role in inflammatory bowel diseases in that it influences inflammatory processes, such as cytokine secretion and immune cell activation. These effects are characterized by an often contrasting function of CRF1 and CRF2. We will review the current data on the expression of CRF and related peptides in the different regions of the gastrointestinal tract, both in normal and inflamed conditions. We next discuss the possible functional roles of CRF signaling in inflammation. The available data clearly indicate that CRF signaling significantly influences inflammatory processes although there are important species and inflammation model differences. Although further research is necessary to elucidate this apparently delicately balanced system, it can be concluded that CRF-related peptides and receptors are (certainly) important candidates in the modulation of gastrointestinal inflammation.
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Affiliation(s)
- Roeland Buckinx
- Laboratory of Cell Biology and Histology, University of Antwerp Antwerp, Belgium
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33
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Salim SY, Söderholm JD. Importance of disrupted intestinal barrier in inflammatory bowel diseases. Inflamm Bowel Dis 2011; 17:362-81. [PMID: 20725949 DOI: 10.1002/ibd.21403] [Citation(s) in RCA: 441] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2010] [Accepted: 06/01/2010] [Indexed: 12/12/2022]
Abstract
The current paradigm of inflammatory bowel diseases (IBD), both Crohn's disease (CD) and ulcerative colitis (UC), involves the interaction between environmental factors in the intestinal lumen and inappropriate host immune responses in genetically predisposed individuals. The intestinal mucosal barrier has evolved to maintain a delicate balance between absorbing essential nutrients while preventing the entry and responding to harmful contents. In IBD, disruptions of essential elements of the intestinal barrier lead to permeability defects. These barrier defects exacerbate the underlying immune system, subsequently resulting in tissue damage. The epithelial phenotype in active IBD is very similar in CD and UC. It is characterized by increased secretion of chloride and water, leading to diarrhea, increased permeability via both the transcellular and paracellular routes, and increased apoptosis of epithelial cells. The main cytokine that seems to drive these changes is tumor necrosis factor alpha in CD, whereas interleukin (IL)-13 may be more important in UC. Therapeutic restoration of the mucosal barrier would provide protection and prevent antigenic overload due to intestinal "leakiness." Here we give an overview of the key players of the intestinal mucosal barrier and review the current literature from studies in humans and human systems on mechanisms underlying mucosal barrier dysfunction in IBD.
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Affiliation(s)
- Sa'ad Y Salim
- Department of Clinical and Experimental Medicine, Division of Surgery and Clinical Oncology, Faculty of Health Sciences, Linköping University, Linköping, Sweden
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Wu SV, Yuan PQ, Lai J, Wong K, Chen MC, Ohning GV, Taché Y. Activation of Type 1 CRH receptor isoforms induces serotonin release from human carcinoid BON-1N cells: an enterochromaffin cell model. Endocrinology 2011; 152:126-37. [PMID: 21123435 PMCID: PMC3219048 DOI: 10.1210/en.2010-0997] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
CRH and 5-hydroxytryptamine (5-HT) are expressed in human colonic enterochromaffin (EC) cells, but their interactions at the cellular level remain largely unknown. The mechanistic and functional relationship between CRH and 5-HT systems in EC cells was investigated in a human carcinoid cloned BON cell line (BON-1N), widely used as an in vitro model of EC cell function. First, we identified multiple CRH(1) splice variants, including CRH(1a), CRH(1c), CRH(1f), and a novel form lacking exon 4, designated here as CRH(1i), in the BON-1N cells. The expression of CRH(1i) was also confirmed in human brain cortex, pituitary gland, and ileum. Immunocytochemistry and immunoblot analysis confirmed that BON-1N cells were CRH(1) and 5-HT positive. CRH, urocortin (Ucn)-1, and cortagine, a selective CRH(1) agonist, all increased intracellular cAMP, and this concentration-dependent response was inhibited by CRH(1)-selective antagonist NBI-35965. CRH and Ucn-1, but not Ucn-2, stimulated significant ERK1/2 phosphorylation. In transfected human embryonic kidney-293 cells, CRH(1i) isoforms produced a significant increase in pERK1/2 in response to CRH(1) agonists that was sensitive to NBI-35965. CRH and Ucn-1 stimulated 5-HT release that reached a maximal increase of 3.3- and 4-fold at 10(-8) m over the basal level, respectively. In addition, exposure to CRH for 24-h up-regulated tryptophan hydroxylase-1 mRNA levels in the BON-1N cells. These findings define the expression of EC cell-specific CRH(1) isoforms and activation of CRH(1)-dependent pathways leading to 5-HT release and synthesis; thus, providing functional evidence of a link exists between CRH and 5-HT systems, which have implications in stress-induced CRH(1) and 5-HT-mediated stimulation of lower intestinal function.
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Affiliation(s)
- S Vincent Wu
- CURE, Building 115, Room 217, Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, California 90073, USA.
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Chaniotou Z, Giannogonas P, Theoharis S, Teli T, Gay J, Savidge T, Koutmani Y, Brugni J, Kokkotou E, Pothoulakis C, Karalis KP. Corticotropin-releasing factor regulates TLR4 expression in the colon and protects mice from colitis. Gastroenterology 2010; 139:2083-92. [PMID: 20732324 DOI: 10.1053/j.gastro.2010.08.024] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2009] [Revised: 07/09/2010] [Accepted: 08/12/2010] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Defects in the colonic innate immune response have been associated with inflammatory bowel disease (IBD). Corticotropin-releasing hormone (CRH, or corticotropin-releasing factor [CRF]) is a neuropeptide that mediates the stress response in humans, is an immunomodulatory factor with proinflammatory effects, and regulates transcription of Toll-like receptors (TLR)-2 and TLR4. We investigated the role of CRF in an innate immunity-dependent mouse model of IBD. METHODS Crh(-/-) and wild-type (Crh(+/+)) mice, which are glucocorticoid insufficient, were given dextran sodium sulfate in their drinking water to induce colitis; in some experiments, mice were also given glucocorticoids. Phenotypes of mice were compared; tissues were analyzed by histology and for expression of immune mediators. RESULTS Crh(-/-) mice had more colonic inflammation than Crh(+/+) mice, characterized by reduced numbers of crypts and severe epithelial damage and ulcerations. Colonic tissue levels of the proinflammatory factors interleukin-12 and prostaglandin E(2) were increased in the Crh(-/-) mice. Colons of Crh(-/-) mice expressed lower levels of Tlr4 than wild-type mice before, but not after, colitis was induced. Administration of glucocorticoid at low levels did not prevent Crh(-/-) mice from developing severe colitis. Crh(-/-) mice were unable to recover from acute colitis, as indicated by their increased death rate. CONCLUSIONS Mice deficient in CRF down-regulate TLR4 and are more susceptible to dextran sodium sulfate-induced colitis. CRF has anti-inflammatory effects in innate immunity-dependent colitis and its recovery phase; these are independent of glucocorticoid administration. CRF might therefore be developed as a therapeutic target for patients with IBD.
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Affiliation(s)
- Zoi Chaniotou
- Developmental Biology Section, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
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Abstract
BACKGROUND The ability to control uptake across the mucosa and protect from damage of harmful substances from the lumen is defined as intestinal barrier function. A disturbed barrier dysfunction has been described in many human diseases and animal models, for example, inflammatory bowel disease, irritable bowel syndrome, and intestinal hypersensitivity. In most diseases and models, alterations are seen both of the paracellular pathway, via the tight junctions, and of the transcellular routes, via different types of endocytosis. Recent studies of pathogenic mechanisms have demonstrated the important role of neuroimmune interaction with the epithelial cells in the regulation of barrier function. Neural impulses from extrinsic vagal and/or sympathetic efferent fibers or intrinsic enteric nerves influence mucosal barrier function via direct effects on epithelial cells or via interaction with immune cells. For example, by nerve-mediated activation by corticotropin-releasing hormone or cholinergic pathways, mucosal mast cells release a range of mediators with effects on transcellular, and/or paracellular permeability (for example, tryptase, TNF-alpha, nerve growth factor, and interleukins). PURPOSE In this review, we discuss current physiological and pathophysiological aspects of the intestinal barrier and, in particular, its regulation by neuroimmune factors.
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Affiliation(s)
- A V Keita
- Department of Clinical and Experimental Medicine, Division of Surgery and Clinical Oncology, Faculty of Health Science, University Hospital, Linköping, Sweden
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Yuan PQ, Wu SV, Wang L, Taché Y. Corticotropin releasing factor in the rat colon: expression, localization and upregulation by endotoxin. Peptides 2010; 31:322-31. [PMID: 19944726 PMCID: PMC2814976 DOI: 10.1016/j.peptides.2009.11.012] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2009] [Revised: 11/12/2009] [Accepted: 11/16/2009] [Indexed: 12/23/2022]
Abstract
Little is known about CRF expression and regulation in the rat colon compared to the brain. We investigated CRF gene expression, cellular location, and regulation by endotoxin and corticosterone in the male rat colon at 6h after intraperitoneal (ip) injection. CRF mRNA level, detected by reverse transcription-polymerase chain reaction (RT-PCR) was 1.3-fold higher in the distal than proximal colon and 3.4-fold higher in the proximal colonic submucosa plus muscle layers than in mucosa. CRF immunoreactivity was located in the epithelia, lamina propria and crypts, and co-localized with tryptophan hydroxylase, a marker for enterochromaffin (EC) cells, and in enteric neurons. Lipopolysaccharide (LPS, 100 microg/kg, ip) increased defecation by 2.9-fold and upregulated CRF mRNA by 2.5-fold in the proximal and 1.1-fold in the distal colon while there was no change induced by corticosterone as monitored by quantitative PCR. LPS-induced increased CRF mRNA expression occurred in the submucosa plus muscle layers (1.5-fold) and the mucosa of proximal colon (0.9-fold). LPS increased significantly CRF immunoreactivity in the submucosal and myenteric plexuses of proximal and distal colon compared to saline groups. These results indicate that in rats, CRF is expressed in both proximal and distal colon and more prominently in enteric neurons of the submucosa plus muscle layers and subject to upregulation at the gene and protein levels by LPS through corticosteroid independent pathways. These data suggests that colonic CRF may be part of the local effector limb of the CRF(1) receptor mediated colonic alterations induced by acute stress.
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Affiliation(s)
- P-Q Yuan
- Center for Neurobiology of Stress, VA Greater Los Angeles Healthcare System, and Digestive Diseases Division, Department of Medicine and Brain Research Institute, University of California Los Angeles, Los Angeles, CA 90073, USA.
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Peripheral relays in stress-induced activation of visceral afferents in the gut. Auton Neurosci 2010; 153:99-105. [DOI: 10.1016/j.autneu.2009.07.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2009] [Revised: 07/06/2009] [Accepted: 07/07/2009] [Indexed: 12/23/2022]
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Kiank C, Taché Y, Larauche M. Stress-related modulation of inflammation in experimental models of bowel disease and post-infectious irritable bowel syndrome: role of corticotropin-releasing factor receptors. Brain Behav Immun 2010; 24:41-8. [PMID: 19698778 PMCID: PMC2962412 DOI: 10.1016/j.bbi.2009.08.006] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2009] [Revised: 08/07/2009] [Accepted: 08/14/2009] [Indexed: 12/14/2022] Open
Abstract
The interaction between gut inflammatory processes and stress is gaining increasing recognition. Corticotropin-releasing factor (CRF)-receptor activation in the brain is well established as a key signaling pathway initiating the various components of the stress response including in the viscera. In addition, a local CRF signaling system has been recently established in the gut. This review summarize the present knowledge on mechanisms through which both brain and gut CRF receptors modulate intestinal inflammatory processes and its relevance towards increased inflammatory bowel disease (IBD) activity and post-infectious irritable bowel syndrome (IBS) susceptibility induced by stress.
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Affiliation(s)
- Cornelia Kiank
- David Geffen School of Medicine at UCLA, CURE: Digestive Diseases Research Center-Animal Core, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.
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Abstract
PURPOSE OF REVIEW Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition, the pathophysiology of which is not well understood. It has, however, become increasingly evident that interactions between the enteric nervous system and the immune system play an important role in the cause of IBD. Both the enteric nervous system and the central nervous system can amplify or modulate the aspects of intestinal inflammation through secretion of neuropeptides or small molecules. The purpose of this study is to present recent data on the role that neuropeptides play in the pathophysiology of IBD. RECENT FINDINGS The best studied of the neuropeptides thought to play a role in the pathogenesis of IBD include substance P, corticotropin-releasing hormone, neurotensin, and vasoactive intestinal peptide; small molecules include acetylcholine and serotonin. Recently discovered functions of each of these neuropeptides with a discussion of implications of the data for therapy are reviewed. SUMMARY Although the available data suggest an important role for neuropeptides in the pathophysiology of intestinal inflammation, there does yet not appear to be a function that can be taken as established for any of these molecules. The complexity of neuroimmune-endocrine systems, conflicting study results and dual mechanisms of action, warrant further research in this field. Clarification of the molecular mechanisms of action of neuropeptides and on immune and inflammatory reactions will likely yield new treatment options in the future.
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Stengel A, Taché Y. Neuroendocrine control of the gut during stress: corticotropin-releasing factor signaling pathways in the spotlight. Annu Rev Physiol 2009; 71:219-39. [PMID: 18928406 DOI: 10.1146/annurev.physiol.010908.163221] [Citation(s) in RCA: 114] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Stress affects the gastrointestinal tract as part of the visceral response. Various stressors induce similar profiles of gut motor function alterations, including inhibition of gastric emptying, stimulation of colonic propulsive motility, and hypersensitivity to colorectal distension. In recent years, substantial progress has been made in our understanding of the underlying mechanisms of stress's impact on gut function. Activation of corticotropin-releasing factor (CRF) signaling pathways mediates both the inhibition of upper gastrointestinal (GI) and the stimulation of lower GI motor function through interaction with different CRF receptor subtypes. Here, we review how various stressors affect the gut, with special emphasis on the central and peripheral CRF signaling systems.
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Affiliation(s)
- Andreas Stengel
- Department of Medicine and CURE Digestive Diseases Research Center, Center for Neurobiology of Stress, University of California at Los Angeles, and VA Greater Los Angeles Healthcare System, Los Angeles, California 90073, USA
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Paschos KA, Kolios G, Chatzaki E. The corticotropin-releasing factor system in inflammatory bowel disease: prospects for new therapeutic approaches. Drug Discov Today 2009; 14:713-20. [PMID: 19379831 DOI: 10.1016/j.drudis.2009.04.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2008] [Revised: 04/01/2009] [Accepted: 04/06/2009] [Indexed: 12/16/2022]
Abstract
Mounting evidence suggests that stress is implicated in the development of inflammatory bowel disease (IBD), via initial nervous disturbance and subsequent immune dysfunction through brain-gut interactions. The corticotropin-releasing factor (CRF) system, being the principal neuroendocrine coordinator of stress responses, is involved in the inflammatory process within the gastrointestinal tract, via vagal and peripheral pathways, as implied by multiple reports reviewed here. Blocking of CRF receptors could theoretically exert beneficial anti-inflammatory effects in colonic tissues. The recently synthesised small-molecule CRF(1) antagonists or alternatively non-peptide CRF(2) antagonists when available, may become new reliable options in the treatment of IBD.
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Affiliation(s)
- Konstantinos A Paschos
- Laboratory of Pharmacology, Faculty of Medicine, Laboratory of Pharmacology, Democritus University of Thrace (DUTH), DUTH, Dragana, Alexandroupolis 68100, Thrace, Greece
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Grover M, Herfarth H, Drossman DA. The functional-organic dichotomy: postinfectious irritable bowel syndrome and inflammatory bowel disease-irritable bowel syndrome. Clin Gastroenterol Hepatol 2009; 7:48-53. [PMID: 18848909 DOI: 10.1016/j.cgh.2008.08.032] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2008] [Revised: 08/08/2008] [Accepted: 08/24/2008] [Indexed: 02/06/2023]
Abstract
Gastroenterologists often encounter situations when the clinical and pathophysiological features that typically distinguish functional from organic disorders overlap. This "blurring of boundaries" can occur with post-infectious irritable bowel syndrome (PI-IBS), a subset of IBS and a newly described entity IBD-IBS. The key associating features include pain and usually diarrheal symptoms that are disproportionate to the observed pathology, microscopic inflammation, and often a co-association with psychological distress. A previous initiating gastrointestinal infection is required for PI-IBS and assumed for IBD-IBS. Using this perspective we discuss the clinical and pathophysiological features of PI-IBS and IBD-IBS and the growing evidence for the overlapping features of these two disorders in terms of alteration of gut flora, immune dysregulation, and role of stress. A unifying model of PI-IBS and IBD-IBS is proposed that may have important clinical and research implications. It obligates us to reframe our understanding of illness and disease from the dualistic biomedical model into a more integrated biopsychosocial (BPS) perspective.
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Affiliation(s)
- Madhusudan Grover
- Center for Functional GI and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7080, USA
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Goetzl EJ, Chan RC, Yadav M. Diverse Mechanisms and Consequences of Immunoadoption of Neuromediator Systems. Ann N Y Acad Sci 2008; 1144:56-60. [DOI: 10.1196/annals.1418.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Santos J, Yates D, Guilarte M, Vicario M, Alonso C, Perdue MH. Stress neuropeptides evoke epithelial responses via mast cell activation in the rat colon. Psychoneuroendocrinology 2008; 33:1248-56. [PMID: 18691825 DOI: 10.1016/j.psyneuen.2008.07.002] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2008] [Revised: 06/11/2008] [Accepted: 07/01/2008] [Indexed: 12/13/2022]
Abstract
BACKGROUND Previously, we showed that corticotropin-releasing factor (CRF) injected i.p. mimicked epithelial responses to stress, both stimulating ion secretion and enhancing permeability in the rat colon, and mast cells were involved. However, the ability of CRF-sensitive mucosal/submucosal loops to regulate intestinal barrier and the participation of resident mast cells are unclear. METHODS We examined colonic epithelial responses to stress-like peptides in Wistar-Kyoto (WKY), and mast cell-deficient (Ws/Ws) and their +/+ littermate control rats in distal segments mounted in Ussing chambers. Short-circuit current (ion secretion), flux of horseradish peroxidase (macromolecular permeability), and the release of rat mast cell protease II were measured in response to CRF [10(-6) to 10(-8)M] or sauvagine [10(-8) to 10(-10)M] in tissues pretreated with astressin, doxantrazole, or vehicle. RESULTS Stress-like peptides (sauvagine > CRF) induced a dose-dependent increase in short-circuit current (maximal at 30 min), and significantly enhanced horseradish peroxidase flux and protease II release in WKY. Epithelial responses were inhibited by both astressin and doxantrazole, and significantly reduced in tissues from Ws/Ws rats. CONCLUSION The stress mediators CRF and sauvagine modulate barrier function in the rat colon acting on mucosal/submucosal CRF receptor-bearing cells, through mast cell-dependent pathways.
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Affiliation(s)
- Javier Santos
- Digestive Diseases Research Unit, Institut de Recerça Vall d'Hebron, Department of Gastroenterology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Department of Medicine, Barcelona, Spain.
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LaBerge J, Malley SE, Girard B, Corrow K, Vizzard MA. Postnatal expression of corticotropin releasing factor (CRF) in rat urinary bladder. Auton Neurosci 2008; 141:83-93. [PMID: 18595780 DOI: 10.1016/j.autneu.2008.05.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2008] [Revised: 05/20/2008] [Accepted: 05/21/2008] [Indexed: 12/12/2022]
Abstract
Corticotropin releasing factor (CRF) is a neuropeptide expressed in micturition reflex circuitry and different roles in these reflexes have been suggested. These studies examined the expression of CRF/CRF receptors in the urinary bladder during postnatal development in the rat. Urinary bladder was harvested from rats (postnatal (P) day 0-adult) euthanized by isoflurane (4%) and thoracotomy. CRF protein expression significantly (p<or=0.01) decreased in the urothelium with increasing postnatal age. In contrast, CRF-immunoreactivity (IR) was increased in nerve fibers in the suburothelial plexus during the second-third postnatal week. Total CRF protein from urinary bladder significantly increased during the second-third postnatal weeks as determined with ELISAs. CRF receptor 2 (CRFR(2)) transcript was expressed in urinary bladder of all postnatal ages examined whereas no CRFR(1) transcript was expressed at any postnatal age examined. We also demonstrated changes in urinary bladder mRNA expression for the neuropeptides, galanin, substance P, vasoactive intestinal polypeptide and pituitary adenylate cyclase activating polypeptide during postnatal development. These studies demonstrate changes in the CRF expression in urinary bladder, specifically in the urothelium and nerve fibers of the suburothelial plexus during postnatal development. Changes in CRF expression and neuropeptide expression in general in the urinary bladder may contribute to the emergence of mature voiding reflexes.
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Affiliation(s)
- Jennifer LaBerge
- Department of Neurology, University of Vermont College of Medicine, Burlington, VT 05405, USA
| | - Susan E Malley
- Department of Neurology, University of Vermont College of Medicine, Burlington, VT 05405, USA
| | - Beatrice Girard
- Department of Anatomy, University of Vermont College of Medicine, Burlington, VT 05405, USA; Department of Anatomy, University of Vermont College of Medicine, Burlington, VT 05405, USA
| | - Kimberly Corrow
- Department of Neurology, University of Vermont College of Medicine, Burlington, VT 05405, USA
| | - Margaret A Vizzard
- Department of Anatomy, University of Vermont College of Medicine, Burlington, VT 05405, USA; Department of Anatomy, University of Vermont College of Medicine, Burlington, VT 05405, USA; Department of Neurology, University of Vermont College of Medicine, Burlington, VT 05405, USA.
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Gay J, Kokkotou E, O'Brien M, Pothoulakis C, Karalis KP. Corticotropin-releasing hormone deficiency is associated with reduced local inflammation in a mouse model of experimental colitis. Endocrinology 2008; 149:3403-9. [PMID: 18403481 PMCID: PMC2453096 DOI: 10.1210/en.2007-1703] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
CRH, the hypothalamic component of the hypothalamic-pituitary adrenal axis, attenuates inflammation through stimulation of glucocorticoid release, whereas peripherally expressed CRH acts as a proinflammatory mediator. CRH is expressed in the intestine and up-regulated in patients with ulcerative colitis. However, its pathophysiological significance in intestinal inflammatory diseases has just started to emerge. In a mouse model of acute, trinitrobenzene sulfonic acid-induced experimental colitis, we demonstrate that, despite low glucocorticoid levels, CRH-deficient mice develop substantially reduced local inflammatory responses. These effects were shown by histological scoring of tissue damage and neutrophil infiltration. At the same time, CRH deficiency was found to be associated with higher serum leptin and IL-6 levels along with sustained anorexia and weight loss, although central CRH has been reported to be a strong appetite suppressor. Taken together, our results support an important proinflammatory role for CRH during mouse experimental colitis and possibly in inflammatory bowel disease in humans. Moreover, the results suggest that CRH is involved in homeostatic pathways that link inflammation and metabolism.
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Affiliation(s)
- Jérôme Gay
- Division of Endocrinology, Children's Hospital, Boston, MA 02215, USA
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Matsuyama M, Yoshimura R. The Target of 5-Lipoxygenase is a Novel Strategy over Human Urological Tumors than the Target of Cyclooxygenase-2. Drug Target Insights 2008. [DOI: 10.4137/dti.s672] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Affiliation(s)
- Masahide Matsuyama
- Department of Urology, Osaka City University Graduate School of Medicine, Add: 1–4–3 Asahi-machi, Abeno-ku, Osaka, 545–8585, Japan
| | - Rikio Yoshimura
- Department of Urology, Osaka City University Graduate School of Medicine, Add: 1–4–3 Asahi-machi, Abeno-ku, Osaka, 545–8585, Japan
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