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Docsa T, Sipos A, Cox CS, Uray K. The Role of Inflammatory Mediators in the Development of Gastrointestinal Motility Disorders. Int J Mol Sci 2022; 23:6917. [PMID: 35805922 PMCID: PMC9266627 DOI: 10.3390/ijms23136917] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/20/2022] [Accepted: 06/20/2022] [Indexed: 02/04/2023] Open
Abstract
Feeding intolerance and the development of ileus is a common complication affecting critically ill, surgical, and trauma patients, resulting in prolonged intensive care unit and hospital stays, increased infectious complications, a higher rate of hospital readmission, and higher medical care costs. Medical treatment for ileus is ineffective and many of the available prokinetic drugs have serious side effects that limit their use. Despite the large number of patients affected and the consequences of ileus, little progress has been made in identifying new drug targets for the treatment of ileus. Inflammatory mediators play a critical role in the development of ileus, but surprisingly little is known about the direct effects of inflammatory mediators on cells of the gastrointestinal tract, and many of the studies are conflicting. Understanding the effects of inflammatory cytokines/chemokines on the development of ileus will facilitate the early identification of patients who will develop ileus and the identification of new drug targets to treat ileus. Thus, herein, we review the published literature concerning the effects of inflammatory mediators on gastrointestinal motility.
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Affiliation(s)
- Tibor Docsa
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.D.); (A.S.)
| | - Adám Sipos
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.D.); (A.S.)
| | - Charles S. Cox
- Department of Pediatric Surgery, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77204, USA;
| | - Karen Uray
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.D.); (A.S.)
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Al-Shargabi T, Govindan RB, Dave R, Metzler M, Wang Y, du Plessis A, Massaro AN. Inflammatory cytokine response and reduced heart rate variability in newborns with hypoxic-ischemic encephalopathy. J Perinatol 2017; 37:668-672. [PMID: 28252659 PMCID: PMC5446303 DOI: 10.1038/jp.2017.15] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 12/04/2016] [Accepted: 12/19/2016] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To determine whether systemic inflammation-modulating cytokine expression is related to heart rate variability (HRV) in newborns with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN The data from 30 newborns with HIE were analyzed. Cytokine levels (IL-2, IL-4, IL-6, IL-8, IL-10, IL-13, IL-1β, TNF-α, IFN-λ) were measured either at 24 h of cooling (n=5), 72 h of cooling (n=4) or at both timepoints (n=21). The following HRV metrics were quantified in the time domain: alpha_S, alpha_L, root mean square (RMS) at short time scales (RMS_S), RMS at long time scales (RMS_L), while low-frequency power (LF) and high-frequency power (HF) were quantified in the frequency domain. The relationships between HRV metrics and cytokines were evaluated using mixed-models. RESULT IL-6, IL-8, IL-10, and IL-13 levels were inversely related to selected HRV metrics. CONCLUSION Inflammation-modulating cytokines may be important mediators in the autonomic dysfunction observed in newborns with HIE.
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Affiliation(s)
- Tareq Al-Shargabi
- Division of Fetal and Transitional Medicine, Fetal Medicine Institute, Children’s National Health System, Washington, United States
| | - R. B. Govindan
- Division of Fetal and Transitional Medicine, Fetal Medicine Institute, Children’s National Health System, Washington, United States,The George Washington University, Washington, DC, United States
| | - Rhiya Dave
- The George Washington University, Washington, DC, United States
| | - Marina Metzler
- Division of Fetal and Transitional Medicine, Fetal Medicine Institute, Children’s National Health System, Washington, United States
| | - Yunfei Wang
- Division of Biostatistics and Study Methodology, Children’s National Health System, Washington, DC, United States
| | - Adre du Plessis
- Division of Fetal and Transitional Medicine, Fetal Medicine Institute, Children’s National Health System, Washington, United States,The George Washington University, Washington, DC, United States
| | - An N. Massaro
- Division of Fetal and Transitional Medicine, Fetal Medicine Institute, Children’s National Health System, Washington, United States,Division of Neonatology, Children’s National Health System, Washington, DC, United States,The George Washington University, Washington, DC, United States,Dr. An N. Massaro, MD, Division of Neonatology, Children’s National Health System, 111 Michigan Ave, NW, Washington, DC 20010, United States, Phone: +1-202-476-5448, Fax: +1-202-476-3459,
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Baldassarre ME, Di Mauro A, Mastromarino P, Fanelli M, Martinelli D, Urbano F, Capobianco D, Laforgia N. Administration of a Multi-Strain Probiotic Product to Women in the Perinatal Period Differentially Affects the Breast Milk Cytokine Profile and May Have Beneficial Effects on Neonatal Gastrointestinal Functional Symptoms. A Randomized Clinical Trial. Nutrients 2016; 8:nu8110677. [PMID: 27801789 PMCID: PMC5133065 DOI: 10.3390/nu8110677] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Revised: 10/14/2016] [Accepted: 10/17/2016] [Indexed: 12/12/2022] Open
Abstract
Background: Probiotic supplementation to women during pregnancy and lactation can modulate breast milk composition, with immune benefits being transferred to their infants. Aim: The aim of the study was to evaluate the effect of high-dose probiotic supplementation to women during late pregnancy and lactation on cytokine profile and secretory IgA (sIgA) in breast milk and thus to study if differences in breast milk composition can affect lactoferrin and sIgA levels in stool samples of newborns. The safety of maternal probiotic administration on neonatal growth pattern and gastrointestinal symptoms were also evaluated. Methods: In a double-blind, placebo-controlled, randomized trial, 66 women took either the probiotic (n = 33) or a placebo (n = 33) daily. Levels of interleukins (IL-6, IL-10 and IL-1β), transforming growth factor-β1 (TGF-β1), and sIgA in breast milk; and the level of sIgA and lactoferrin in newborn stool samples were analyzed at birth and then again at one month of life. Antropometrical evaluation and analysis of gastrointestinal events in newborns was also performed. Results: Probiotic maternal consumption had a significant impact on IL6 mean values in colostrum and on IL10 and TGF-β1 mean values in mature breast milk. Fecal sIgA mean values were higher in newborns whose mothers took the probiotic product than in the control group. Probiotic maternal supplementation seems to decrease incidence of infantile colic and regurgitation in infants. Conclusion: High-dose multi-strain probiotic administration to women during pregnancy influences breast milk cytokines pattern and sIgA production in newborns, and seems to improve gastrointestinal functional symptoms in infants.
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Affiliation(s)
- Maria Elisabetta Baldassarre
- Department of Biomedical Science and Human Oncology, Neonatology and Neonatal Intensive Care Unit, "Aldo Moro" University of Bari, Bari 70100, Italy.
| | - Antonio Di Mauro
- Department of Biomedical Science and Human Oncology, Neonatology and Neonatal Intensive Care Unit, "Aldo Moro" University of Bari, Bari 70100, Italy.
| | - Paola Mastromarino
- Department of Public Health and Infectious Disease, "Sapienza" University of Rome, Rome 00100, Italy.
| | - Margherita Fanelli
- Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, Bari 70100, Italy.
| | - Domenico Martinelli
- Department of Biomedical Science and Human Oncology, Neonatology and Neonatal Intensive Care Unit, "Aldo Moro" University of Bari, Bari 70100, Italy.
| | - Flavia Urbano
- Department of Biomedical Science and Human Oncology, Neonatology and Neonatal Intensive Care Unit, "Aldo Moro" University of Bari, Bari 70100, Italy.
| | - Daniela Capobianco
- Department of Public Health and Infectious Disease, "Sapienza" University of Rome, Rome 00100, Italy.
| | - Nicola Laforgia
- Department of Biomedical Science and Human Oncology, Neonatology and Neonatal Intensive Care Unit, "Aldo Moro" University of Bari, Bari 70100, Italy.
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4
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McLean LP, Smith A, Cheung L, Urban JF, Sun R, Grinchuk V, Desai N, Zhao A, Raufman JP, Shea-Donohue T. Type 3 muscarinic receptors contribute to intestinal mucosal homeostasis and clearance of Nippostrongylus brasiliensis through induction of TH2 cytokines. Am J Physiol Gastrointest Liver Physiol 2016; 311:G130-41. [PMID: 27173511 PMCID: PMC4967171 DOI: 10.1152/ajpgi.00461.2014] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 05/06/2016] [Indexed: 01/31/2023]
Abstract
Despite increased appreciation for the role of nicotinic receptors in the modulation of and response to inflammation, the contribution of muscarinic receptors to mucosal homeostasis, clearance of enteric pathogens, and modulation of immune cell function remains relatively undefined. Uninfected and Nippostrongylus brasiliensis-infected wild-type and type 3 muscarinic receptor (M3R)-deficient (Chrm3(-/-)) mice were studied to determine the contribution of M3R to mucosal homeostasis as well as host defense against the TH2-eliciting enteric nematode N. brasiliensis Intestinal permeability and expression of TH1/TH17 cytokines were increased in uninfected Chrm3(-/-) small intestine. Notably, in Chrm3(-/-) mice infected with N. brasiliensis, small intestinal upregulation of TH2 cytokines was attenuated and nematode clearance was delayed. In Chrm3(-/-) mice, TH2-dependent changes in small intestinal function including smooth muscle hypercontractility, increased epithelial permeability, decreased epithelial secretion and absorption, and goblet cell expansion were absent despite N. brasiliensis infection. These findings identify an important role for M3R in host defense and clearance of N. brasiliensis, and support the expanding role of cholinergic muscarinic receptors in maintaining mucosal homeostasis.
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MESH Headings
- Animals
- Cells, Cultured
- Cytokines/immunology
- Cytokines/metabolism
- Disease Models, Animal
- Genetic Predisposition to Disease
- Homeostasis
- Host-Pathogen Interactions
- Immunity, Mucosal
- Intestinal Mucosa/immunology
- Intestinal Mucosa/metabolism
- Intestinal Mucosa/parasitology
- Intestine, Small/immunology
- Intestine, Small/metabolism
- Intestine, Small/parasitology
- Macrophage Activation
- Macrophages/immunology
- Macrophages/metabolism
- Macrophages/parasitology
- Mice, 129 Strain
- Mice, Inbred C57BL
- Mice, Knockout
- Nippostrongylus/immunology
- Nippostrongylus/pathogenicity
- Phenotype
- Receptor, Muscarinic M3/deficiency
- Receptor, Muscarinic M3/genetics
- Receptor, Muscarinic M3/metabolism
- Strongylida Infections/genetics
- Strongylida Infections/immunology
- Strongylida Infections/metabolism
- Strongylida Infections/parasitology
- Th2 Cells/immunology
- Th2 Cells/metabolism
- Th2 Cells/parasitology
- Time Factors
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Affiliation(s)
- Leon P McLean
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Allen Smith
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, Maryland; and
| | - Lumei Cheung
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, Maryland; and
| | - Joseph F Urban
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, Maryland; and
| | - Rex Sun
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Viktoriya Grinchuk
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Neemesh Desai
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Aiping Zhao
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Jean-Pierre Raufman
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Terez Shea-Donohue
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland; Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland
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5
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Farro G, Gomez-Pinilla PJ, Di Giovangiulio M, Stakenborg N, Auteri M, Thijs T, Depoortere I, Matteoli G, Boeckxstaens GE. Smooth muscle and neural dysfunction contribute to different phases of murine postoperative ileus. Neurogastroenterol Motil 2016; 28:934-47. [PMID: 26891411 DOI: 10.1111/nmo.12796] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 01/15/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND Postoperative ileus (POI) is characterized by a transient inhibition of gastrointestinal (GI) motility after abdominal surgery mediated by the inflammation of the muscularis externa (ME). The aim of this study was to identify alterations in the enteric nervous system that may contribute to the pathogenesis of POI. METHODS Gastrointestinal transit, contractility of isolated smooth muscle strips and inflammatory parameters were evaluated at different time points (1.5 h to 10 days) after intestinal manipulation (IM) in mice. Immune-labeling was used to visualize changes in myenteric neurons. KEY RESULTS Intestinal manipulation resulted in an immediate inhibition of GI transit recovering between 24 h and 5 days. In vitro contractility to K(+) (60 mM) or carbachol (10(-9) to 10(-4) M) was biphasically suppressed over 24 h after IM (with transient recovery at 6 h). The first phase of impaired myogenic contractility was associated with increased expression of TNF-α, IL-6 and IL-1α. After 24 h, we identified a significant reduction in electrical field stimulation-evoked contractions and relaxations, lasting up to 10 days after IM. This was associated with a reduced expression of chat and nos1 genes. CONCLUSIONS & INFERENCES Intestinal manipulation induces two waves of smooth muscle inhibition, most likely mediated by inflammatory cytokines, lasting up to 3 days after IM. Further, we here identify a late third phase (>24 h) characterized by impaired cholinergic and nitrergic neurotransmission persisting after recovery of muscle contractility. These findings illustrate that POI results from inflammation-mediated impaired smooth muscle contraction, but also involves a long-lasting impact of IM on the enteric nervous system.
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Affiliation(s)
- G Farro
- Division of Gastroenterology, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - P J Gomez-Pinilla
- Division of Gastroenterology, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - M Di Giovangiulio
- Division of Gastroenterology, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - N Stakenborg
- Division of Gastroenterology, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - M Auteri
- Division of Physiology, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - T Thijs
- Division of Gastroenterology, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - I Depoortere
- Division of Gastroenterology, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - G Matteoli
- Division of Gastroenterology, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - G E Boeckxstaens
- Division of Gastroenterology, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
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6
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Affiliation(s)
- Pamela J Hornby
- Janssen Research & Development, Cardiovascular and Metabolic Disease, Janssen Pharmaceutical Companies of Johnson and Johnson, SH42-2508-A, 1400 McKean Road, Spring House, PA 19477, USA
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7
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Laermans J, Broers C, Beckers K, Vancleef L, Steensels S, Thijs T, Tack J, Depoortere I. Shifting the circadian rhythm of feeding in mice induces gastrointestinal, metabolic and immune alterations which are influenced by ghrelin and the core clock gene Bmal1. PLoS One 2014; 9:e110176. [PMID: 25329803 PMCID: PMC4199674 DOI: 10.1371/journal.pone.0110176] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Accepted: 09/12/2014] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND In our 24-hour society, an increasing number of people are required to be awake and active at night. As a result, the circadian rhythm of feeding is seriously compromised. To mimic this, we subjected mice to restricted feeding (RF), a paradigm in which food availability is limited to short and unusual times of day. RF induces a food-anticipatory increase in the levels of the hunger hormone ghrelin. We aimed to investigate whether ghrelin triggers the changes in body weight and gastric emptying that occur during RF. Moreover, the effect of genetic deletion of the core clock gene Bmal1 on these physiological adaptations was studied. METHODS Wild-type, ghrelin receptor knockout and Bmal1 knockout mice were fed ad libitum or put on RF with a normal or high-fat diet (HFD). Plasma ghrelin levels were measured by radioimmunoassay. Gastric contractility was studied in vitro in muscle strips and in vivo (13C breath test). Cytokine mRNA expression was quantified and infiltration of immune cells was assessed histologically. RESULTS The food-anticipatory increase in plasma ghrelin levels induced by RF with normal chow was abolished in HFD-fed mice. During RF, body weight restoration was facilitated by ghrelin and Bmal1. RF altered cytokine mRNA expression levels and triggered contractility changes resulting in an accelerated gastric emptying, independent from ghrelin signaling. During RF with a HFD, Bmal1 enhanced neutrophil recruitment to the stomach, increased gastric IL-1α expression and promoted gastric contractility changes. CONCLUSIONS This is the first study demonstrating that ghrelin and Bmal1 regulate the extent of body weight restoration during RF, whereas Bmal1 controls the type of inflammatory infiltrate and contractility changes in the stomach. Disrupting the circadian rhythm of feeding induces a variety of diet-dependent metabolic, immune and gastrointestinal alterations, which may explain the higher prevalence of obesity and immune-related gastrointestinal disorders among shift workers.
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Affiliation(s)
- Jorien Laermans
- Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium
| | - Charlotte Broers
- Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium
| | - Kelly Beckers
- Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium
| | - Laurien Vancleef
- Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium
| | - Sandra Steensels
- Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium
| | - Theo Thijs
- Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium
| | - Jan Tack
- Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium
| | - Inge Depoortere
- Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium
- * E-mail:
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Al-Qudah M, Anderson CD, Mahavadi S, Bradley ZL, Akbarali HI, Murthy KS, Grider JR. Brain-derived neurotrophic factor enhances cholinergic contraction of longitudinal muscle of rabbit intestine via activation of phospholipase C. Am J Physiol Gastrointest Liver Physiol 2014; 306:G328-37. [PMID: 24356881 PMCID: PMC3920121 DOI: 10.1152/ajpgi.00203.2013] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of proteins best known for its role in neuronal survival, differentiation, migration, and synaptic plasticity in central and peripheral neurons. BDNF is also widely expressed in nonneuronal tissues including the gastrointestinal tract. The role of BDNF in intestinal smooth muscle contractility is not well defined. The aim of this study was to identify the role of BDNF in carbachol (CCh)- and substance P (SP)-induced contraction of intestinal longitudinal smooth muscle. BDNF, selective tropomyosin-related kinase B (TrkB) receptor agonists, and pharmacological inhibitors of signaling pathways were examined for their effects on contraction of rabbit intestinal longitudinal muscle strips induced by CCh and SP. BDNF activation of intracellular signaling pathways was examined by Western blot in homogenates of muscle strips and isolated muscle cells. One-hour preincubation with BDNF enhanced intestinal muscle contraction induced by CCh but not by SP. The selective synthetic TrkB agonists LM 22A4 and 7,8-dihydroxyflavone produced similar effects to BDNF. The Trk antagonist K-252a, a TrkB antibody but not p75NTR antibody, blocked the effect of BDNF. The enhancement of CCh-induced contraction by BDNF was blocked by the phospholipase C (PLC) antagonist U73122, but not by ERK1/2 or Akt antagonists. Direct measurement in muscle strips and isolated muscle cells showed that BDNF caused phosphorylation of TrkB receptors and PLC-γ, but not ERK1/2 or Akt. We conclude that exogenous BDNF augments the CCh-induced contraction of longitudinal muscle from rabbit intestine by activating TrkB receptors and subsequent PLC activation.
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Affiliation(s)
- M. Al-Qudah
- 1Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia; ,3Jordan University of Science and Technology, Irbid, Jordan
| | - C. D. Anderson
- 1Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia;
| | - S. Mahavadi
- 1Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia;
| | - Z. L. Bradley
- 1Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia;
| | - H. I. Akbarali
- 2Department of Pharmacology and Toxicology, VCU Program in Enteric Neuromuscular Sciences (VPENS), School of Medicine, Virginia Commonwealth University, Richmond, Virginia; and
| | - K. S. Murthy
- 1Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia;
| | - J. R. Grider
- 1Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia;
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9
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Alkahtani R, Mahavadi S, Al-Shboul O, Alsharari S, Grider JR, Murthy KS. Changes in the expression of smooth muscle contractile proteins in TNBS- and DSS-induced colitis in mice. Inflammation 2013; 36:1304-15. [PMID: 23794034 PMCID: PMC3823744 DOI: 10.1007/s10753-013-9669-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Thin filament-associated proteins such as calponin, caldesmon, tropomyosin, and smoothelin are thought to regulate acto-myosin interaction and thus, muscle contraction. However, the effect of inflammation on the expression of thin filament-associated proteins is not known. The aim of the present study is to determine the changes in the expression of calponin, caldesmon, tropomyosin, and smoothelin in colonic smooth muscle from trinitrobenzene sulphonic acid (TNBS)- and dextran sodium sulphate (DSS)-induced colitis in mice. Expression of h-caldesmon, h2-calponin, α-tropomyosin, and smoothelin-A was measured by qRT-PCR and Western blot. Contraction in response to acetylcholine in dispersed muscle cells was measured by scanning micrometry. mRNA and protein expression of α-actin, h2-calponin, h-caldesmon, smoothelin, and α-tropomyosin in colonic muscle strips from mice with TNBS- or DSS-induced colitis was significantly increased compared to control animals. Contraction in response to acetylcholine was significantly decreased in muscle cells isolated from inflamed regions of TNBS- or DSS-treated mice compared to control mice. Our results show that increase in the expression of thin filament-associated contractile proteins, which inhibit acto-myosin interaction, could contribute to decrease in smooth muscle contraction in inflammation.
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Affiliation(s)
- Reem Alkahtani
- Department of Physiology, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia
| | - Sunila Mahavadi
- Department of Physiology, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia
| | - Othman Al-Shboul
- Department of Physiology, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia
| | - Shakir Alsharari
- Department of Pharmacology, Virginia Commonwealth University, Richmond, Virginia
| | - John R. Grider
- Department of Physiology, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia
| | - Karnam S. Murthy
- Department of Physiology, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia
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10
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Yang Z, Sun R, Grinchuk V, Fernández-Blanco JA, Blanco JAF, Notari L, Bohl JA, McLean LP, Ramalingam TR, Wynn TA, Urban JF, Vogel SN, Shea-Donohue T, Zhao A. IL-33-induced alterations in murine intestinal function and cytokine responses are MyD88, STAT6, and IL-13 dependent. Am J Physiol Gastrointest Liver Physiol 2013; 304:G381-9. [PMID: 23257921 PMCID: PMC3566613 DOI: 10.1152/ajpgi.00357.2012] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2012] [Accepted: 12/12/2012] [Indexed: 01/31/2023]
Abstract
IL-33 is a recently identified cytokine member of the IL-1 family. The biological activities of IL-33 are associated with promotion of Th2 and inhibition of Th1/Th17 immune responses. Exogenous IL-33 induces a typical "type 2" immune response in the gastrointestinal tract, yet the underlying mechanisms remain to be fully elucidated. In addition, the role of IL-33 in the regulation of gastrointestinal function is not known. The present study investigated IL-33-dependent intestinal immunity and function in mice. Exogenous IL-33 induced a polarized type 2 cytokine response in the intestine that was entirely MyD88 dependent but STAT6 and IL-13 independent. Mice injected with recombinant IL-33 exhibited intestinal smooth muscle hypercontractility, decreased epithelial responses to acetylcholine and glucose, and increased mucosal permeability. IL-33 effects on intestinal epithelial function were STAT6 dependent, and both IL-4 and IL-13 appeared to play a role. The effects on smooth muscle function, however, were attributable to both STAT6-dependent and -independent mechanisms. In addition, IL-13 induction of insulin-like growth factor-1 was implicated in IL-33-induced smooth muscle hypertrophy. Finally, alternative activation of macrophages induced by IL-33 revealed a novel pathway that is IL-4, IL-13, and STAT6 independent. Thus manipulating IL-33 or related signaling pathways represents a potential therapeutic strategy for treating inflammatory diseases associated with dysregulated intestinal function.
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Affiliation(s)
- Zhonghan Yang
- Department of Medicine and the Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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11
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Abstract
BACKGROUND Inflammation-induced changes in smooth muscle may be the consequence of changes in the properties of smooth muscle itself, in the control by nerves and hormones, in the microenvironment, or in the balance of constitutive or induced mediators. A general concept is that the specific characteristics and effects of inflammation can be linked to the nature of the infiltrate and the associated mediators, which are dictated predominantly by the immune environment. Inflammatory mediators may regulate smooth muscle function by directly acting on smooth muscle cells or, indirectly, through stimulation of the release of mediators from other cells. In addition, smooth muscle is not a passive bystander during inflammation and our knowledge of molecular signaling pathways that control smooth muscle function, and the contribution of the immune mechanisms to smooth muscle homeostasis, has expanded greatly in the last decade. Recent studies also demonstrated the relevance of extracellular proteases, of endogenous or exogenous origin, redox imbalance, or epigenetic mechanisms, to gastrointestinal dismotility and inflammation in the context of functional and organic disorders. PURPOSE In this review we discuss the various types of inflammation and the established and emerging mechansims of inflammation-induced changes in smooth muscle morphology and function.
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Affiliation(s)
- T Shea-Donohue
- Mucosal Biology Research Center and Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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12
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Thomson ABR, Chopra A, Clandinin MT, Freeman H. Recent advances in small bowel diseases: Part II. World J Gastroenterol 2012; 18:3353-74. [PMID: 22807605 PMCID: PMC3396188 DOI: 10.3748/wjg.v18.i26.3353] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2011] [Revised: 04/05/2012] [Accepted: 04/13/2012] [Indexed: 02/06/2023] Open
Abstract
As is the case in all areas of gastroenterology and hepatology, in 2009 and 2010 there were many advances in our knowledge and understanding of small intestinal diseases. Over 1000 publications were reviewed, and the important advances in basic science as well as clinical applications were considered. In Part II we review six topics: absorption, short bowel syndrome, smooth muscle function and intestinal motility, tumors, diagnostic imaging, and cystic fibrosis.
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Scott GD, Fryer AD. Role of parasympathetic nerves and muscarinic receptors in allergy and asthma. CHEMICAL IMMUNOLOGY AND ALLERGY 2012; 98:48-69. [PMID: 22767057 DOI: 10.1159/000336498] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Parasympathetic nerves control the symptoms and inflammation of allergic diseases primarily by signaling through peripheral muscarinic receptors. Parasympathetic signaling targets classic effector tissues such as airway smooth muscle and secretory glands and mediates acute symptoms of allergic disease such as airway narrowing and increased mucus secretion. In addition, parasympathetic signaling modulates inflammatory cells and non-neuronal resident cell types such as fibroblasts and smooth muscle contributing to chronic allergic inflammation and tissue remodeling. Importantly, muscarinic antagonists are experiencing a rebirth for the treatment of asthma and may be useful for treating other allergic diseases.
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Affiliation(s)
- Gregory D Scott
- Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, OR 97239, USA
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14
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Akiho H, Ihara E, Motomura Y, Nakamura K. Cytokine-induced alterations of gastrointestinal motility in gastrointestinal disorders. World J Gastrointest Pathophysiol 2011; 2:72-81. [PMID: 22013552 PMCID: PMC3196622 DOI: 10.4291/wjgp.v2.i5.72] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2011] [Revised: 08/12/2011] [Accepted: 08/19/2011] [Indexed: 02/06/2023] Open
Abstract
Inflammation and immune activation in the gut are usually accompanied by alteration of gastrointestinal (GI) motility. In infection, changes in motor function have been linked to host defense by enhancing the expulsion of the infectious agents. In this review, we describe the evidence for inflammation and immune activation in GI infection, inflammatory bowel disease, ileus, achalasia, eosinophilic esophagitis, microscopic colitis, celiac disease, pseudo-obstruction and functional GI disorders. We also describe the possible mechanisms by which inflammation and immune activation in the gut affect GI motility. GI motility disorder is a broad spectrum disturbance of GI physiology. Although several systems including central nerves, enteric nerves, interstitial cells of Cajal and smooth muscles contribute to a coordinated regulation of GI motility, smooth muscle probably plays the most important role. Thus, we focus on the relationship between activation of cytokines induced by adaptive immune response and alteration of GI smooth muscle contractility. Accumulated evidence has shown that Th1 and Th2 cytokines cause hypocontractility and hypercontractility of inflamed intestinal smooth muscle. Th1 cytokines downregulate CPI-17 and L-type Ca2+ channels and upregulate regulators of G protein signaling 4, which contributes to hypocontractility of inflamed intestinal smooth muscle. Conversely, Th2 cytokines cause hypercontractilty via signal transducer and activator of transcription 6 or mitogen-activated protein kinase signaling pathways. Th1 and Th2 cytokines have opposing effects on intestinal smooth muscle contraction via 5-hydroxytryptamine signaling. Understanding the immunological basis of altered GI motor function could lead to new therapeutic strategies for GI functional and inflammatory disorders.
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15
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Milara J, Serrano A, Peiró T, Gavaldà A, Miralpeix M, Morcillo EJ, Cortijo J. Aclidinium inhibits human lung fibroblast to myofibroblast transition. Thorax 2011; 67:229-37. [PMID: 21957094 PMCID: PMC3282044 DOI: 10.1136/thoraxjnl-2011-200376] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background Fibroblast to myofibroblast transition is believed to contribute to airway remodelling in lung diseases such as asthma and chronic obstructive pulmonary disease. This study examines the role of aclidinium, a new long-acting muscarinic antagonist, on human fibroblast to myofibroblast transition. Methods Human bronchial fibroblasts were stimulated with carbachol (10−8 to 10−5 M) or transforming growth factor-β1 (TGF-β1; 2 ng/ml) in the presence or absence of aclidinium (10−9 to 10−7 M) or different drug modulators for 48 h. Characterisation of myofibroblasts was performed by analysis of collagen type I and α-smooth muscle actin (α-SMA) mRNA and protein expression as well as α-SMA microfilament immunofluorescence. ERK1/2 phosphorylation, RhoA-GTP and muscarinic receptors (M) 1, 2 and 3 protein expression were determined by western blot analysis and adenosine 3′-5′ cyclic monophosphate levels were determined by ELISA. Proliferation and migration of fibroblasts were also assessed. Results Collagen type I and α-SMA mRNA and protein expression, as well as percentage α-SMA microfilament-positive cells, were upregulated in a similar way by carbachol and TGF-β1, and aclidinium reversed these effects. Carbachol-induced myofibroblast transition was mediated by an increase in ERK1/2 phosphorylation, RhoA-GTP activation and cyclic monophosphate downregulation as well as by the autocrine TGF-β1 release, which were effectively reduced by aclidinium. TGF-β1 activated the non-neuronal cholinergic system. Suppression of M1, M2 or M3 partially prevented carbachol- and TGF-β1-induced myofibroblast transition. Aclidinium dose-dependently reduced fibroblast proliferation and migration. Conclusion Aclidinium inhibits human lung fibroblast to myofibrobast transition.
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Affiliation(s)
- Javier Milara
- Unidad de Investigación, Consorcio Hospital General, Universitario, Avenida Tres Vruces s/n, Valencia E-46014, Spain.
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16
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Akiho H, Ihara E, Nakamura K. Low-grade inflammation plays a pivotal role in gastrointestinal dysfunction in irritable bowel syndrome. World J Gastrointest Pathophysiol 2011. [PMID: 21607147 DOI: 10.4291/wjgp.v1.i3.97.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The pathogenesis of irritable bowel syndrome (IBS) is considered to be multifactorial and includes psychosocial factors, visceral hypersensitivity, infection, microbiota and immune activation. It is becoming increasingly clear that low-grade inflammation is present in IBS patients and a number of biomarkers have emerged. This review describes the evidence for low-grade inflammation in IBS and explores its mechanism with particular focus on gastrointestinal motor dysfunction. Understanding of the immunological basis of the altered gastrointestinal motor function in IBS may lead to new therapeutic strategies for IBS.
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Affiliation(s)
- Hirotada Akiho
- Hirotada Akiho, Eikichi Ihara, Kazuhiko Nakamura, Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
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17
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Verdú EF, Bercik P, Collins SM. Effect of probiotics on gastrointestinal function: evidence from animal models. Therap Adv Gastroenterol 2011; 2:31-5. [PMID: 21180552 DOI: 10.1177/1756283x09337645] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
The digestive tract works through a complex net of integrative functions. At the level of the gut, this integration occurs between the immune, neuromotor and endocrine systems, the intestinal barrier and gut luminal contents. Gastrointestinal function is controlled and coordinated by the central nervous system to ensure effective motility, secretion, absorption and mucosal immunity. Thus, it is clear that the gut keeps a tightly regulated equilibrium between luminal stimuli, epithelium, immunity and neurotransmission in order to maintain homeostasis. It follows that perturbations of any of these systems may lead to gut dysfunction. While we acknowledge that the gut-brain axis is crucial in determining coordinated gut function, in this review we will focus on peripheral mechanisms that influence gastrointestinal physiology and pathophysiology. We will discuss the general hypothesis that the intestinal content is crucial in determining what we consider normal gastrointestinal physiology, and consequently that alteration in luminal content by dietary, antibiotic or probiotic manipulation can result in changes in gut function. This article focuses on lessons learned from animal models of gut dysfunction.
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Affiliation(s)
- Elena F Verdú
- Department of Medicine, McMaster University, Hamilton, Canada
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18
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Fairchild KD, Srinivasan V, Moorman JR, Gaykema RPA, Goehler LE. Pathogen-induced heart rate changes associated with cholinergic nervous system activation. Am J Physiol Regul Integr Comp Physiol 2010; 300:R330-9. [PMID: 21068197 DOI: 10.1152/ajpregu.00487.2010] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The autonomic nervous system plays a central role in regulation of host defense and in physiological responses to sepsis, including changes in heart rate and heart rate variability. The cholinergic anti-inflammatory response, whereby infection triggers vagal efferent signals that dampen production of proinflammatory cytokines, would be predicted to result in increased vagal signaling to the heart and increased heart rate variability. In fact, decreased heart rate variability is widely described in humans with sepsis. Our studies elucidate this apparent paradox by showing that mice injected with pathogens demonstrate transient bradyarrhythmias of vagal origin in a background of decreased heart rate variability (HRV). Intraperitoneal injection of a large inoculum of Gram-positive or Gram-negative bacteria or Candida albicans rapidly induced bradyarrhythmias of sinus and AV nodal block, characteristic of cardiac vagal firing and dramatically increased short-term HRV. These pathogen-induced bradycardias were immediately terminated by atropine, an antagonist of muscarinic cholinergic receptors, demonstrating the role of vagal efferent signaling in this response. Vagal afferent signaling following pathogen injection was demonstrated by intense nuclear c-Fos activity in neurons of the vagal sensory ganglia and brain stem. Surprisingly, pathogen-induced bradycardia demonstrated rapid and prolonged desensitization and did not recur on repeat injection of the same organism 3 h or 3 days after the initial exposure. After recovery from the initial bradycardia, depressed heart rate variability developed in some mice and was correlated with elevated plasma cytokine levels and mortality. Our findings of decreased HRV and transient heart rate decelerations in infected mice are similar to heart rate changes described by our group in preterm neonates with sepsis. Pathogen sensing and signaling via the vagus nerve, and the desensitization of this response, may account for periods of both increased and decreased heart rate variability in sepsis.
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Affiliation(s)
- Karen D Fairchild
- Dept. of Pediatrics, University of Virginia Health System, Hospital Dr., Charlottesville, VA 22908, USA
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19
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Akiho H, Ihara E, Nakamura K. Low-grade inflammation plays a pivotal role in gastrointestinal dysfunction in irritable bowel syndrome. World J Gastrointest Pathophysiol 2010; 1:97-105. [PMID: 21607147 PMCID: PMC3097950 DOI: 10.4291/wjgp.v1.i3.97] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2010] [Revised: 07/26/2010] [Accepted: 08/02/2010] [Indexed: 02/06/2023] Open
Abstract
The pathogenesis of irritable bowel syndrome (IBS) is considered to be multifactorial and includes psychosocial factors, visceral hypersensitivity, infection, microbiota and immune activation. It is becoming increasingly clear that low-grade inflammation is present in IBS patients and a number of biomarkers have emerged. This review describes the evidence for low-grade inflammation in IBS and explores its mechanism with particular focus on gastrointestinal motor dysfunction. Understanding of the immunological basis of the altered gastrointestinal motor function in IBS may lead to new therapeutic strategies for IBS.
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20
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Buchholz BM, Bauer AJ. Membrane TLR signaling mechanisms in the gastrointestinal tract during sepsis. Neurogastroenterol Motil 2010; 22:232-45. [PMID: 20377787 PMCID: PMC2951022 DOI: 10.1111/j.1365-2982.2009.01464.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Our bacterial residents are deadly Janus-faced indwellers that can lead to a sepsis-induced systemic inflammatory response syndrome and multiple organ failure. Over half of ICU patients suffer from infections and sepsis remains one of the top 10 causes of death worldwide. Severe ileus frequently accompanies sepsis setting up an insidious cycle of gut-derived microbial translocation and the copious intestinal production of potent systemic inflammatory mediators. Few therapeutic advances have occurred to prevent/treat the sequelae of sepsis. Here, we selectively review studies on cellular membrane-bound Toll-like receptor (TLR) mechanisms of ileus. Virtually, no data exist on Gram-positive/TLR2 signaling mechanisms of ileus; however, TLR2 is highly inducible by numerous inflammatory mediators and studies using clinically relevant scenarios of Gram-positive sepsis are needed. Specific Gram-negative/TLR4 signaling pathways are being elucidated using a 'reverse engineering' approach, which has revealed that endotoxin-induced ileus is dually mediated by classical leukocyte signaling and by a MyD88-dependent non-bone marrow-derived mechanism, but the specific roles of individual cell populations are still unknown. Like TLR2, little is also know of the role of flagellin/TLR5 signaling in ileus. But, much can be learned by understanding TLR signaling in other systems. Clearly, the use of polymicrobial models provides important clinical relevancy, but the simultaneous activation of virtually all pattern recognition receptors makes it impossible to discretely study specific pathways. We believe that the dissection of individual TLR pathways within the gastrointestinal tract, which can then be intelligently reassembled in a meaningful manner, will provide insight into treatments for sepsis.
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Affiliation(s)
- Bettina M. Buchholz
- Department of Medicine/Gastroenterology, University of Pittsburgh, Pittsburgh, PA, Department of Surgery, Rheinische Friedrich-Wilhelms-Universität Bonn, Germany
| | - Anthony J. Bauer
- Department of Medicine/Gastroenterology, University of Pittsburgh, Pittsburgh, PA
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21
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Mizutani T, Akiho H, Khan WI, Murao H, Ogino H, Kanayama K, Nakamura K, Takayanagi R. Persistent gut motor dysfunction in a murine model of T-cell-induced enteropathy. Neurogastroenterol Motil 2010; 22:196-203, e65. [PMID: 19735478 DOI: 10.1111/j.1365-2982.2009.01396.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) patients in remission often experience irritable bowel syndrome (IBS)-like symptoms. We investigated the mechanism for intestinal muscle hypercontractility seen in T-cell-induced enteropathy in recovery phase. METHODS BALB/c mice were treated with an anti-CD3 antibody (100 microg per mouse) and euthanized at varying days post-treatment to investigate the histological changes, longitudinal smooth muscle cell contraction, cytokines (Th1, Th2 cytokines, TNF-alpha) and serotonin (5-HT)-expressing enterochromaffin cell numbers in the small intestine. The role of 5-HT in anti-CD3 antibody-induced intestinal muscle function in recovery phase was assessed by inhibiting 5-HT synthesis using 4-chloro-DL-phenylalanine (PCPA). KEY RESULTS Small intestinal tissue damage was observed from 24 h after the anti-CD3 antibody injection, but had resolved by day 5. Carbachol-induced smooth muscle cell contractility was significantly increased from 4 h after injection, and this muscle hypercontractility was evident in recovery phase (at day 7). Th2 cytokines (IL-4, IL-13) were significantly increased from 4 h to day 7. 5-HT-expressing cells in the intestine were increased from day 1 to day 7. The 5-HT synthesis inhibitor PCPA decreased the anti-CD3 antibody-induced muscle hypercontractility in recovery phase. CONCLUSIONS & INFERENCES Intestinal muscle hypercontractility in remission is maintained at the smooth muscle cell level. Th2 cytokines and 5-HT in the small intestine contribute to the maintenance of the altered muscle function in recovery phase.
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Affiliation(s)
- T Mizutani
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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22
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Józsa T, Magyar A, Cserni T, Szentmiklósi AJ, Erdélyi K, Kincses Z, Rákóczy G, Balla G, Roszer T. Short-term adaptation of rat intestine to ileostomy: implication for pediatric practice. J INVEST SURG 2010; 22:292-300. [PMID: 19842906 DOI: 10.1080/08941930903040106] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
BACKGROUND Surgical neonates with complex intestinal conditions, such as enterocolitis, midgut volvulus with bowel loss and multiple atresias, often require temporary stomas. Little is known on the postsurgical response of the altered gut segments, although adaptation is an important consideration in neonatal postoperative care, particularly after stoma closure. MATERIALS AND METHODS Rats underwent bowel resection at a point 15 cm proximal to the ileocecal valve, and a split ileostomy was performed. On the 6th postoperative day the mucosal thickness was calculated with Soft Imaging System Analysis Pro, the rate of proliferation was measured following Ki67 immunohistochemistry and the apoptotic index was determined on sections stained with ApopTag Plus. The intestinal motor activity was recorded on isolated gut segments. Neuronal nitric oxide synthase (nNOS) expression and distribution was examined with NADPH-diaphorase histochemistry and Western blot analysis. RESULTS An increased wet weight of the mucosa and a pronounced mucosal thickening were observed in the proximal functional bowel segment. Enterocyte proliferation rate was increased significantly, while the apoptotic index remained unchanged in the epithelial layer. The dilation of the gut lumen resulted in a morphological change in the nitrergic myenteric network with an overexpression of nNOS. As a consequence of the surgical procedure, the functional proximal gut segment showed strong and frequent contraction waves, with an enhanced responsiveness to cholinergic stimuli. CONCLUSIONS The dilated functional bowel segment was characterized by hyperplasic changes in the mucosa and stronger mechanical activity with overproduction of nNOS. Although early restoration of intestinal continuity is recommended, our observations on adaptive changes may partly explain intestinal motility disorders after early stoma closure, suggesting the need for a careful approach to a redo-laparotomy.
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Affiliation(s)
- Tamás Józsa
- Department of Pediatrics, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary. jozsa
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Shea-Donohue T, Fasano A, Smith A, Zhao A. Enteric pathogens and gut function: Role of cytokines and STATs. Gut Microbes 2010; 1:316-324. [PMID: 21327040 PMCID: PMC3023616 DOI: 10.4161/gmic.1.5.13329] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2010] [Revised: 01/18/2010] [Accepted: 05/12/2010] [Indexed: 02/03/2023] Open
Abstract
The gut harbors the largest immune system in the body. The mucosa is considered to be the initial site of interaction with commensal and pathogenic organisms; therefore, it is the first line of defense against the pathogens. In response to the invasion of various pathogens, naïve CD4(+) cells differentiate into subsets of T helper (Th) cells that are characterized by different cytokine profiles. Cytokines bind to cell surface receptors on both immune and non-immune cells leading to activation of JAK-STAT signaling pathway and influence gut function by upregulating the expression of specific target genes. This review considers the roles of cytokines and receptor-mediated activation of STATs on pathogen-induced changes in gut function. The focus on STAT4 and STAT6 is because of their requirement for the full development of Th1 and Th2 cytokine profiles.
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Affiliation(s)
- Terez Shea-Donohue
- Department of Medicine; University of Maryland School of Medicine, Baltimore, MD USA,Mucosal Biology Research Center; University of Maryland School of Medicine, Baltimore, MD USA
| | - Alessio Fasano
- Department of Pediatrics; University of Maryland School of Medicine, Baltimore, MD USA,Mucosal Biology Research Center; University of Maryland School of Medicine, Baltimore, MD USA
| | - Allen Smith
- Beltsville Human Nutrition Research Center; USDA; Beltsville, MD USA
| | - Aiping Zhao
- Department of Medicine; University of Maryland School of Medicine, Baltimore, MD USA,Mucosal Biology Research Center; University of Maryland School of Medicine, Baltimore, MD USA
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Valeur J, Lappalainen J, Rita H, Lin AH, Kovanen PT, Berstad A, Eklund KK, Vaali K. Food allergy alters jejunal circular muscle contractility and induces local inflammatory cytokine expression in a mouse model. BMC Gastroenterol 2009; 9:33. [PMID: 19450258 PMCID: PMC2689247 DOI: 10.1186/1471-230x-9-33] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2008] [Accepted: 05/18/2009] [Indexed: 02/01/2023] Open
Abstract
Background We hypothesized that food allergy causes a state of non-specific jejunal dysmotility. This was tested in a mouse model. Methods Balb/c mice were epicutaneously sensitized with ovalbumin and challenged with 10 intragastric ovalbumin administrations every second day. Smooth muscle contractility of isolated circular jejunal sections was studied in organ bath with increasing concentrations of carbamylcholine chloride (carbachol). Smooth muscle layer thickness and mast cell protease-1 (MMCP-1) positive cell density were assayed histologically. Serum MMCP-1 and immunoglobulins were quantified by ELISA, and mRNA expressions of IFN-γ, IL-4, IL-6 and TGFβ-1 from jejunal and ileal tissue segments were analyzed with quantitative real-time PCR. Results Ovalbumin-specific serum IgE correlated with jejunal MMCP-1+ cell density. In the allergic mice, higher concentrations of carbachol were required to reach submaximal muscular stimulation, particularly in preparations derived from mice with diarrhoea. Decreased sensitivity to carbachol was associated with increased expression of IL-4 and IL-6 mRNA in jejunum. Smooth muscle layer thickness, as well as mRNA of IFN-γ and TGF-β1 remained unchanged. Conclusion In this mouse model of food allergy, we demonstrated a decreased response to a muscarinic agonist, and increased levels of proinflammatory IL-6 and Th2-related IL-4, but not Th1-related IFN-γ mRNAs in jejunum. IgE levels in serum correlated with the number of jejunal MMCP-1+ cells, and predicted diarrhoea. Overall, these changes may reflect a protective mechanism of the gut in food allergy.
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Affiliation(s)
- Jørgen Valeur
- Institute of Medicine, University of Bergen, Bergen, Norway.
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25
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Hu W, Li F, Mahavadi S, Murthy KS. Upregulation of RGS4 expression by IL-1beta in colonic smooth muscle is enhanced by ERK1/2 and p38 MAPK and inhibited by the PI3K/Akt/GSK3beta pathway. Am J Physiol Cell Physiol 2009; 296:C1310-20. [PMID: 19369446 DOI: 10.1152/ajpcell.00573.2008] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Initial Ca(2+)-dependent contraction of intestinal smooth muscle is inhibited upon IL-1beta treatment. The decrease in contraction reflects the upregulation of regulator of G protein signaling-4 (RGS4) via the canonical inhibitor of NF-kappaB kinase-2 (IKK2)/IkappaB-alpha/NF-kappaB pathway. Here, we show that the activation of various protein kinases, including ERK1/2, p38 MAPK, and phosphoinositide 3-kinase (PI3K), differentially modulates IL-1beta-induced upregulation of RGS4 in rabbit colonic muscle cells. IL-1beta treatment caused a transient phosphorylation of ERK1/2 and p38 MAPK. It also caused the phosphorylation of Akt and glycogen synthase kinase-3beta (GSK3beta), sequential downstream effectors of PI3K. Pretreatment with PD-98059 (an ERK inhibitor) and SB-203580 (a p38 MAPK inhibitor) significantly inhibited IL-1beta-induced RGS4 expression. In contrast, LY-294002 (a PI3K inhibitor) augmented, whereas GSK3beta inhibitors inhibited, IL-1beta-induced RGS4 expression. PD-98059 blocked IL-1beta-induced phosphorylation of IKK2, degradation of IkappaB-alpha, and phosphorylation and nuclear translocation of NF-kappaB subunit p65, whereas SB-203580 had a marginal effect, implying that the effect of ERK1/2 is exerted on the canonical IKK2/IkappaB-alpha/p65 pathway of NF-kappaB activation but that the effect of p38 MAPK may not predominantly involve NF-kappaB signaling. The increase in RGS4 expression enhanced by LY-294002 was accompanied by an increase in the phosphorylation of IKK2/IkappaB-alpha/p65 and blocked by pretreatment with inhibitors of IKK2 (IKK2-IV) and IkappaB-alpha (MG-132). Inhibition of GSK3beta abolished IL-1beta-induced phosphorylation of IKK2/p65. These findings suggest that ERK1/2 and p38 MAPK enhance IL-1beta-induced upregulation of RGS4; the effect of ERK1/2 reflects its ability to promote IKK2 phosphorylation and increase NF-kappaB activity. GSK3beta acts normally to augment the activation of the canonical NF-kappaB signaling. The PI3K/Akt/GSK3beta pathway attenuates IL-1beta-induced upregulation of RGS4 expression by inhibiting NF-kappaB activation.
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Affiliation(s)
- Wenhui Hu
- Department of Physiology and Biophysics, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia, USA.
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26
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Gregersen K, Lind RA, Bjørkkjaer T, Frøyland L, Berstad A, Lied GA. Effects of Seal Oil on Meal-Induced Symptoms and Gastric Accommodation in Patients with Subjective Food Hypersensitivity: A Pilot Study. ACTA ACUST UNITED AC 2008. [DOI: 10.4137/cgast.s1028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Background Food hypersensitivity is a prevalent condition with poorly characterized underlying mechanisms. In the present pilot study we investigated effects of seal oil and soy oil on meal-induced symptoms and gastric accommodation in patients with subjective food hypersensitivity (FH). Single dose experiment: On three consecutive days, 10 mL of seal oil, soy oil, or saline were randomly administered into the duodenum of 10 patients with subjective FH and 10 healthy volunteers through a nasoduodenal feeding tube 10-20 minutes before the ingestion of a test meal. Short-term treatment study: 24 patients with subjective FH were randomly allocated to 10 days’ treatment with either 10 mL of seal or soy oil, self-administrated through an indwelling nasoduodenal feeding tube, 3 times daily. In both experiments meal-induced abdominal symptoms and gastric accommodation were measured by visual analogue scales and external ultrasound respectively. Results Symptoms and gastric accommodation were not significantly influenced by single doses of seal or soy oil. When given daily for 10 days, seal oil, but not soy oil, reduced total symptom scores significantly ( P = 0.03). The symptomatic improvement was not associated with improvements in gastric accommodation. Conclusion Daily administration of seal oil may benefit patients with subjective FH. The beneficial effect of seal oil in patients with subjective FH can not be ascribed to improved gastric accommodation.
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Affiliation(s)
- Kine Gregersen
- National Institute of Nutrition and Seafood Research (NIFES), PO Box 2029 Nordnes, N-5817 Bergen, Norway
- Institute of Medicine, Haukeland University Hospital, University of Bergen, N-5021 Bergen, Norway
| | - Ragna A. Lind
- Institute of Medicine, Haukeland University Hospital, University of Bergen, N-5021 Bergen, Norway
| | - Tormod Bjørkkjaer
- National Institute of Nutrition and Seafood Research (NIFES), PO Box 2029 Nordnes, N-5817 Bergen, Norway
- Department of Biomedicine, University of Bergen, N-5009 Bergen, Norway
| | - Livar Frøyland
- National Institute of Nutrition and Seafood Research (NIFES), PO Box 2029 Nordnes, N-5817 Bergen, Norway
| | - Arnold Berstad
- Institute of Medicine, Haukeland University Hospital, University of Bergen, N-5021 Bergen, Norway
| | - Gulen Arslan Lied
- Institute of Medicine, Haukeland University Hospital, University of Bergen, N-5021 Bergen, Norway
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Fasina YO, Holt PS, Moran ET, Moore RW, Conner DE, McKee SR. Intestinal cytokine response of commercial source broiler chicks to Salmonella typhimurium infection. Poult Sci 2008; 87:1335-46. [PMID: 18577613 DOI: 10.3382/ps.2007-00526] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Development of molecular-based immunotherapeutic strategies for controlling Salmonella Typhimurium (ST) infection in poultry requires a better understanding of intestinal and cecal cytokine responses. Accordingly, an experiment was conducted to measure changes in intestinal cytokine expression when commercial source broiler chickens were challenged with a nalidixic acid-resistant ST. Ross broiler chicks were nonchallenged with ST (control treatment) or challenged by orally giving 7.8 x 10(6) cfu at 4 d of age (STC treatment). Each treatment consisted of 4 replicate pens with 14 chicks per pen. Expression levels of proinflammatory cytokines, interferon-gamma, and antiinflammatory interleukin (IL)-10 were determined at 5 and 10 d postchallenge (PC). Intestinal flushes were also collected from each treatment at 7 d PC to estimate IgA and IgG. Results showed an upregulation in IL-1beta mRNA in STC chicks at 5 d PC. By 10 d PC, the expression of IL-1beta was further increased and accompanied by an upregulation of IL-6 and interferon-gamma mRNA, whereas IL-10 mRNA expression decreased. It was concluded that ST induced an intestinal mucosal inflammatory response in commercial source broiler chicks less than 2 wk of age.
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Affiliation(s)
- Y O Fasina
- Department of Poultry Science, Auburn University, 260 Lem Morrison Drive, Auburn, AL 36849-5416, USA.
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28
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Soares PMG, Mota JMSC, Gomes AS, Oliveira RB, Assreuy AMS, Brito GAC, Santos AA, Ribeiro RA, Souza MHLP. Gastrointestinal dysmotility in 5-fluorouracil-induced intestinal mucositis outlasts inflammatory process resolution. Cancer Chemother Pharmacol 2008; 63:91-8. [PMID: 18324404 DOI: 10.1007/s00280-008-0715-9] [Citation(s) in RCA: 110] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2007] [Accepted: 02/17/2008] [Indexed: 12/22/2022]
Abstract
AIM To evaluate gastrointestinal motility during 5-fluorouracil (5-FU)-induced intestinal mucositis. MATERIALS AND METHODS Wistar rats received 5-FU (150 mg kg(-1), i.p.) or saline. After the 1st, 3rd, 5th, 15th and 30th day, sections of duodenum, jejunum and ileum were removed for assessment of epithelial damage, apoptotic and mitotic indexes, MPO activity and GSH concentration. In order to study gastrointestinal motility, on the 3rd or 15th day after 5-FU treatment, gastric emptying in vivo was measured by scintilographic method, and stomach or duodenal smooth muscle contractions induced by CCh were evaluated in vitro. RESULTS On the third day of treatment, 5-FU induced a significant villi shortening, an increase in crypt depth and intestinal MPO activity and a decrease in villus/crypt ratio and GSH concentration. On the first day after 5-FU there was an increase in the apoptosis index and a decrease in the mitosis index in all intestinal segments. After the 15th day of 5-FU treatment, a complete reversion of all these parameters was observed. There was a delay in gastric emptying in vivo and a significant increase in gastric fundus and duodenum smooth muscle contraction, after both the 3rd and 15th day. CONCLUSION 5-FU-induced gastrointestinal dysmotility outlasts intestinal mucositis.
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Affiliation(s)
- Pedro M G Soares
- Centro de Biomedicina, Faculdade de Medicina, Universidade Federal do Ceará, Rodolfo Teófilo, Fortaleza, Brazil
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29
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Hu W, Mahavadi S, Li F, Murthy KS. Upregulation of RGS4 and downregulation of CPI-17 mediate inhibition of colonic muscle contraction by interleukin-1beta. Am J Physiol Cell Physiol 2007; 293:C1991-2000. [PMID: 17959727 PMCID: PMC4123227 DOI: 10.1152/ajpcell.00300.2007] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The pro-inflammatory cytokine IL-1beta contributes to the reduced contractile responses of gut smooth muscle observed in both animal colitis models and human inflammatory bowel diseases. However, the mechanisms are not well understood. The effects of IL-1beta on the signaling targets mediating acetylcholine (ACh)-induced initial and sustained contraction were examined using rabbit colonic circular muscle strips and cultured muscle cells. The contraction was assessed through cell length decrease, myosin light chain (MLC(20)) phosphorylation, and activation of PLC-beta and Rho kinase. Expression levels of the signaling targets were determined by Western blot analysis and real-time RT-PCR. Short interfering RNAs (siRNAs) for regulator of G protein signaling 4 (RGS4) were used to silence endogenous RGS4 in muscle strips or cultured muscle cells. IL-1beta treatment of muscle strips inhibited both initial and sustained contraction and MLC(20) phosphorylation in isolated muscle cells. IL-1beta treatment increased RGS4 expression but had no effect on muscarinic receptor binding or Galpha(q) expression. In contrast, IL-1beta decreased the expression and phosphorylation of CPI-17 but had no effect on RhoA expression or ACh-induced Rho kinase activity. Upregulation of RGS4 and downregulation of CPI-17 by IL-1beta in muscle strips were corroborated in cultured muscle cells. Knockdown of RGS4 by siRNA in both muscle strips and cultured muscle cells blocked the inhibitory effect of IL-1beta on initial contraction and PLC-beta activation, whereas overexpression of RGS4 inhibited PLC-beta activation. These data suggest that IL-1beta upregulates RGS4 expression, resulting in the inhibition of initial contraction and downregulation of CPI-17 expression during sustained contraction in colonic smooth muscle.
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Affiliation(s)
- Wenhui Hu
- Department of Physiology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA.
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