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Antibiotics Suppress Activation of Intestinal Mucosal Mast Cells and Reduce Dietary Lipid Absorption in Sprague-Dawley Rats.
Sato H, Zhang LS, Martinez K, Chang EB, Yang Q, Wang F, Howles PN, Hokari R, Miura S, Tso P
(2016) Gastroenterology 151: 923-932
MeSH Terms: Animals, Anti-Bacterial Agents, Dietary Fats, Gastrointestinal Microbiome, Intestinal Absorption, Intestinal Mucosa, Male, Mast Cells, Penicillins, Permeability, Rats, Rats, Sprague-Dawley, Streptomycin
Show Abstract · Added August 5, 2016
BACKGROUND & AIMS - The gut microbiota affects intestinal permeability and mucosal mast cells (MMCs) responses. Activation of MMCs has been associated with absorption of dietary fat. We investigated whether the gut microbiota contributes to the fat-induced activation of MMCs in rats, and how antibiotics might affect this process.
METHODS - Adult male Sprague-Dawley rats were given streptomycin and penicillin for 4 days (n = 6-8) to reduce the abundance of their gut flora, or normal drinking water (controls, n = 6-8). They underwent lymph fistula surgery and after an overnight recovery were given an intraduodenal bolus of intralipid. We collected intestinal tissues and lymph fluid and assessed activation of MMCs, intestinal permeability, and fat transport parameters.
RESULTS - Compared with controls, intestinal lymph from rats given antibiotics had reduced levels of mucosal mast cell protease II (produced by MMCs) and decreased activity of diamine oxidase (produced by enterocytes) (P < .05). Rats given antibiotics had reduced intestinal permeability in response to dietary lipid compared with controls (P < .01). Unexpectedly, antibiotics also reduced lymphatic transport of triacylglycerol and phospholipid (P < .01), concomitant with decreased levels of mucosal apolipoproteins B, A-I, and A-IV (P < .01). No differences were found in intestinal motility or luminal pancreatic lipase activity between rats given antibiotics and controls. These effects were not seen with an acute dose of antibiotics or 4 weeks after the antibiotic regimen ended.
CONCLUSIONS - The intestinal microbiota appears to activate MMCs after the ingestion of fat in rats; this contributes to fat-induced intestinal permeability. We found that the gut microbiome promotes absorption of lipid, probably by intestinal production of apolipoproteins and secretion of chylomicrons.
Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.
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13 MeSH Terms
Selective, α2β1 integrin-dependent secretion of il-6 by connective tissue mast cells.
McCall-Culbreath KD, Li Z, Zhang Z, Lu LX, Orear L, Zutter MM
(2011) J Innate Immun 3: 459-70
MeSH Terms: Animals, Antigens, Bacterial, Calcium Signaling, Cell Degranulation, Cells, Cultured, Connective Tissue, Humans, Immunity, Innate, Immunoglobulin E, Integrin alpha2beta1, Interleukin-6, Listeria monocytogenes, Mast Cells, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptor Aggregation
Show Abstract · Added February 16, 2014
Mast cells, critical mediators of inflammation and anaphylaxis, are poised as one of the first lines of defense against external assault. Mast cells release several classes of preformed and de novo synthesized mediators. Cross-linking of the high-affinity FcεRI results in degranulation and the release of preformed, proinflammatory mediators including histamine and serotonin. We previously demonstrated that mast cell activation by Listeria monocytogenes requires the α2β1 integrin for rapid IL-6 secretion both in vivo and in vitro. However, the mechanism of IL-6 release is unknown. Here, we demonstrate the Listeria- and α2β1 integrin-mediated mast cell release of preformed IL-6 without the concomitant release of histamine or β-hexosaminidase. α2β1 integrin-dependent mast cell activation and IL-6 release is calcium independent. In contrast, IgE cross-linking-mediated degranulation is calcium dependent and does not result in IL-6 release, demonstrating that distinct stimuli result in the release of specific mediator pools. These studies demonstrate that IL-6 is presynthesized and stored in connective tissue mast cells and can be released from mast cells in response to distinct, α2β1 integrin-dependent stimulation, providing the host with a specific innate immune response without stimulating an allergic reaction.
Copyright © 2011 S. Karger AG, Basel.
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17 MeSH Terms
Effect of chronic mild stress on serotonergic markers in the skin and brain of the NC/Nga atopic-like mouse strain.
Rasul A, El-Nour H, Blakely RD, Lonne-Rahm SB, Forsberg J, Johansson B, Theodorsson E, Nordlind K
(2011) Arch Dermatol Res 303: 625-33
MeSH Terms: Animals, Antigens, Dermatophagoides, Brain, Chronic Disease, Dermatitis, Atopic, Disease Susceptibility, Gene Expression Regulation, Mast Cells, Mice, Mice, Inbred Strains, Microscopy, Fluorescence, Receptor, Serotonin, 5-HT1A, Receptor, Serotonin, 5-HT2A, Serotonin, Serotonin Plasma Membrane Transport Proteins, Skin, Stress, Physiological
Show Abstract · Added July 10, 2013
Atopic eczema is often worsened by stress. While acute stress is associated with increased turnover of serotonin (5-hydroxytryptamine; 5-HT), chronic stress causes a decrease. In chronic stress, there is a decrease of the 5-HT1A receptor (R)- and an increase in the 5-HT2AR-responsiveness to 5-HT. In the present study, the impact of chronic mild stress on the expression of 5-HT1A and 5-HT2A receptors and serotonin transporter protein (SERT) was investigated in eczematous skin and brain of atopic-like NC/Nga mice. Twenty-four NC/Nga mice were subjected to chronic mild stress for 12 weeks, and eczema was induced by applying a mite antigen (Dermatophagoides pteronyssinus) on the ears for the last 4 weeks. The mice were divided into three groups, eight per group, stressed eczematous (SE), non-stressed eczematous (NSE) and stressed control (SC). The biopsies were analysed by immunohistochemistry, using a streptavidin-biotin technique. There was an increased number of 5-HT containing dermal mast cell-like mononuclear cells in the skin of mice with eczema (SE and NSE, respectively) compared with the SC, and a tendency to more 5-HT-positive cells in the SE compared with the NSE group. Increased 5-HT1AR immunoreactivity (IR) in the skin and hippocampus of the eczematous groups compared to the control group was seen, but no difference between the SE and NSE groups. The epidermal immunoreactivity for 5-HT2AR was highest in the SE and NSE compared to the SC group, and was also higher in the SE compared to NSE. 5-HT2AR expression was also seen on nerve bundles, the number and intensity of such bundles being decreased in the SE compared to the NSE group. In the CA1 area of the hippocampus, there was an increase in the quantity of cells immunoreactive for 5-HT2AR in the SE versus the NSE group and also in the SE versus the SC group. SERT-IR was found also on nerve bundles with a decreased number in the SE compared to the NSE and SC group. There is a modulation of the expression of serotonergic markers in the eczematous skin and brain of the atopic-like mouse during chronic mild stress.
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17 MeSH Terms
Eosinophils and mast cells in chronic gastritis: possible implications in carcinogenesis.
Piazuelo MB, Camargo MC, Mera RM, Delgado AG, Peek RM, Correa H, Schneider BG, Sicinschi LA, Mora Y, Bravo LE, Correa P
(2008) Hum Pathol 39: 1360-9
MeSH Terms: Adult, Colombia, Eosinophils, Gastric Mucosa, Gastritis, Helicobacter Infections, Helicobacter pylori, Humans, Male, Mast Cells, Middle Aged, Precancerous Conditions, Risk Factors, Stomach Neoplasms
Show Abstract · Added March 5, 2014
Eosinophils and mast cells participate in the immune response against Helicobacter pylori, but their involvement in the gastric precancerous process is unclear. This study aimed to estimate eosinophil and mast cell density in antral mucosa in subjects from 2 Colombian populations with contrasting gastric cancer risks. Gastric mucosa biopsies were collected from 117 adult males (72 from a high-risk area and 45 from a low-risk area). A histopathology score was used to quantify severity of the lesions. Quantitation of eosinophils in hematoxylin-eosin-stained sections and mast cells in immunostained sections for CD117/c-Kit was performed. Helicobacter pylori infection and genotyping were assessed in Steiner stain and polymerase chain reaction, respectively. Logistic regression models and semiparametric cubic smoothing splines were used for analysis of the results. Eosinophil density was significantly higher in subjects from the low-risk area as compared with subjects from the high-risk area. In both populations, eosinophil density increased with the histopathology score in the progression of lesions from normal morphology to multifocal atrophic gastritis. Intestinal metaplasia and dysplasia specimens showed further increase in eosinophil density in the high-risk area but an abrupt decrease in the low-risk area. Mast cell density increased in parallel to the histopathology score in both populations. Our results suggest that eosinophils play a dual role in chronic gastritis. In the low-risk area, elevated eosinophil density represents a T helper 2-biased response that may down-regulate the effects of proinflammatory cytokines preventing cancer development. In contrast, in the high-risk area, eosinophils might promote a T helper 1-type response leading to progression of precancerous lesions.
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14 MeSH Terms
Effect of A2B adenosine receptor gene ablation on proinflammatory adenosine signaling in mast cells.
Ryzhov S, Zaynagetdinov R, Goldstein AE, Novitskiy SV, Dikov MM, Blackburn MR, Biaggioni I, Feoktistov I
(2008) J Immunol 180: 7212-20
MeSH Terms: Adenosine, Adenosine A2 Receptor Antagonists, Adenosine Monophosphate, Animals, Bone Marrow Cells, Cell Degranulation, Cell Line, Cells, Cultured, Extracellular Signal-Regulated MAP Kinases, Humans, Interleukin-13, Mast Cells, Mice, Mice, Inbred C57BL, Purines, Receptor, Adenosine A2B, Signal Transduction, Vascular Endothelial Growth Factor A, Xanthines, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added December 10, 2013
Pharmacological studies suggest that A(2B) adenosine receptors mediate proinflammatory effects of adenosine in human mast cells in part by up-regulating production of Th2 cytokines and angiogenic factors. This concept has been recently challenged by the finding that mast cells cultured from bone marrow-derived mast cells (BMMCs) of A(2B) knockout mice display an enhanced degranulation in response to FcepsilonRI stimulation. This finding was interpreted as evidence of anti-inflammatory functions of A(2B) receptors and it was suggested that antagonists with inverse agonist activity could promote activation of mast cells. In this report, we demonstrate that genetic ablation of the A(2B) receptor protein has two distinct effects on BMMCs, one is the previously reported enhancement of Ag-induced degranulation, which is unrelated to adenosine signaling; the other is the loss of adenosine signaling via this receptor subtype that up-regulates IL-13 and vascular endothelial growth factor secretion. Genetic ablation of A(2B) receptors had no effect on A(3) adenosine receptor-dependent potentiation of Ag-induced degranulation in mouse BMMCs, but abrogated A(2B) adenosine receptor-dependent stimulation of IL-13 and vascular endothelial growth factor secretion. Adenosine receptor antagonists MRS1706 and DPCPX with known inverse agonist activity at the A(2B) subtype inhibited IL-13 secretion induced by the adenosine analog NECA, but did not mimic the enhanced Ag-induced degranulation observed in A(2B) knockout BMMCs. Thus, our study confirmed the proinflammatory role of adenosine signaling via A(2B) receptors and the anti-inflammatory actions of A(2B) antagonists in mouse BMMCs.
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20 MeSH Terms
A protective role of mast cells in intestinal tumorigenesis.
Sinnamon MJ, Carter KJ, Sims LP, Lafleur B, Fingleton B, Matrisian LM
(2008) Carcinogenesis 29: 880-6
MeSH Terms: Animals, Endopeptidases, Female, Intestinal Neoplasms, Male, Mast Cells, Mice, Mice, Inbred C57BL, Polymerase Chain Reaction
Show Abstract · Added March 5, 2014
Mast cells have been observed in numerous types of tumors; however, their role in carcinogenesis remains poorly understood. The majority of epidemiological evidence suggests a negative association between the presence of mast cells and tumor progression in breast, lung and colonic neoplasms. Intestinal adenomas in the multiple intestinal neoplasia (Min, APC(Min/+)) mouse displayed increased numbers of mast cells and increased abundance of mast cell-associated proteinases as determined by transcriptional profiling with the Hu/Mu ProtIn microarray. To examine the role of mast cells in intestinal tumorigenesis, a mutant mouse line deficient in mast cells, Sash mice (c-kit(W-sh/W-sh)), was crossed with the Min mouse, a genetic model of intestinal neoplasia. The resulting mast cell-deficient Min-Sash mice developed 50% more adenomas than littermate controls and the tumors were 33% larger in Min-Sash mice. Mast cell deficiency did not affect tumor cell proliferation; however, apoptosis was significantly inhibited in mast cell-deficient mice. Mast cells have been shown to act as critical upstream regulators of numerous inflammatory cells. Neutrophil, macrophage and T cell populations were similar between Min and Min-Sash mice; however, eosinophils were significantly less abundant in tumors obtained from Min-Sash animals. These results indicate a protective, antitumor role of mast cells in a genetic model of early-stage intestinal tumorigenesis.
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9 MeSH Terms
Crosstalk between the alpha2beta1 integrin and c-met/HGF-R regulates innate immunity.
McCall-Culbreath KD, Li Z, Zutter MM
(2008) Blood 111: 3562-70
MeSH Terms: Animals, Autoimmune Diseases, Bacterial Proteins, Complement C1q, Cytokines, Extracellular Matrix Proteins, Immunity, Innate, Immunologic Capping, Inflammation, Integrin alpha2, Leukocytes, Mononuclear, Listeria monocytogenes, Listeriosis, Mast Cells, Membrane Proteins, Mice, Mice, Knockout, Protein Binding, Proto-Oncogene Proteins c-met, Receptors, IgG, Receptors, Virus
Show Abstract · Added February 16, 2014
Data from several investigators suggest that the alpha2beta1 integrin, a receptor for collagens, laminins, decorin, E-cadherin, matrix metalloproteinase-1, endorepellin, and several viruses, is required for innate immunity and regulation of autoimmune/allergic disorders. We demonstrated that the innate immune response to Listeria monocytogenes required alpha2beta1 integrin expression by peritoneal mast cells (PMCs). Ligation of the alpha2beta1 integrin by C1q contained in immune complexes comprised of Listeria and antibody was required for PMC activation in vitro and in vivo. However, ligation of the alpha2beta1 integrin alone was insufficient to activate cytokine secretion, suggesting that one or more additional signals emanating from a coreceptor were required for PMC activation. Here, we demonstrate that C1q, but neither other complement proteins nor FcRgamma, is required for early innate immune response to Listeria. The binding of Listeria's Internalin B (InlB) to hepatocyte growth factor receptor (HGF-R)/c-met provides the costimulatory function required for PMC activation. Either HGF or Listeria InlB bound to c-met and either C1q or type I collagen bound to alpha2beta1 integrin stimulates PMC activation. These findings suggest that crosstalk between c-met and the alpha2beta1 integrin may contribute to mast-cell activation in autoimmune and inflammatory disorders.
1 Communities
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21 MeSH Terms
The alpha2beta1 integrin: a novel collectin/C1q receptor.
Zutter MM, Edelson BT
(2007) Immunobiology 212: 343-53
MeSH Terms: Animals, Collectins, Humans, Immunity, Innate, Integrin alpha2beta1, Interleukin-6, Mast Cells, Membrane Glycoproteins, Receptors, Complement
Show Abstract · Added February 16, 2014
Our laboratory focuses on the alpha2beta1 integrin, a receptor for a number of matrix and non-matrix ligands, including collagens, laminins, decorin, E-cadherin, matrix metalloproteinase-1 (MMP-1), endorepellin, and several viruses. The alpha2beta1 integrin is expressed on numerous different cell types, including epithelial cells, endothelial cells, fibroblasts, and hematopoietic elements, including platelets and specific subsets of leukocytes. Although alpha2beta1 integrin expression is widespread, it is not ubiquitous. Rather, it is expressed in a differentiation-dependent and activation-dependent manner. Interactions between the alpha2beta1 integrin and extracellular matrix ligands have been implicated in important biological processes including inflammation and immunity. Studies from a number of laboratories have demonstrated a role for the alpha2beta1 integrin during the immune response. Our laboratory generated an alpha2beta1 integrin-deficient mouse to define the role of the alpha2beta1 integrin in vivo. Our studies demonstrated that the alpha2-null mice have a profound defect in the innate immune response. We have recently reported the identification of a novel family of ligands for the alpha2beta1 integrin, which include C1q and the collectins. The goal of this article is to review the important role that the interaction between the alpha2beta1 integrin and C1q plays in the innate immune response. The identification of C1q and the collectins as ligands for the alpha2beta1 integrin suggests that the integrin may play important roles in a number of immunological responses.
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9 MeSH Terms
Integrin alpha2beta1 is required for regulation of murine wound angiogenesis but is dispensable for reepithelialization.
Zweers MC, Davidson JM, Pozzi A, Hallinger R, Janz K, Quondamatteo F, Leutgeb B, Krieg T, Eckes B
(2007) J Invest Dermatol 127: 467-78
MeSH Terms: Animals, Cells, Cultured, Cicatrix, Collagen, Epithelium, Fibroblasts, Integrin alpha2beta1, Integrins, Mast Cells, Mice, Mice, Inbred C57BL, Mice, Knockout, Neovascularization, Physiologic, Skin, Wound Healing, Wounds, Penetrating
Show Abstract · Added February 24, 2014
The alpha2beta1 integrin functions as the major receptor for collagen type I on a large number of different cell types, including keratinocytes, fibroblasts, endothelial cells, and a variety of inflammatory cells. Recently, we demonstrated that adhesion of keratinocytes to collagen critically depends on alpha2beta1, whereas fibroblasts can partly compensate for loss of alpha2beta1 in simple adhesion to collagen. However, in three-dimensional collagen matrices, alpha2beta1-null fibroblasts are hampered in generating mechanical forces. These data suggested a pivotal role for alpha2beta1 during wound healing in vivo. Unexpectedly, reepithelialization of excisional wounds of alpha2beta1-null mice was not impaired, indicating that keratinocytes do not require adhesion to or migration on collagen for wound closure. Whereas wound contraction and myofibroblast differentiation were similar, wound tensile strain was reduced in alpha2beta1-null mice, suggesting subtle changes in organization of the extracellular matrix. In addition, we observed reduced influx of mast cells into the granulation tissue, whereas infiltration of other inflammatory cells was not impaired. Interestingly, ablation of alpha2beta1 resulted in strong enhancement of neovascularization of granulation tissue and sponge implants. Both ultrastructurally and functionally, these new blood vessels appeared intact. In conclusion, our data show unique and overlapping functions of alpha2beta1 integrin during murine cutaneous wound healing.
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16 MeSH Terms
Cross-talk between G(s)- and G(q)-coupled pathways in regulation of interleukin-4 by A(2B) adenosine receptors in human mast cells.
Ryzhov S, Goldstein AE, Biaggioni I, Feoktistov I
(2006) Mol Pharmacol 70: 727-35
MeSH Terms: Adenosine-5'-(N-ethylcarboxamide), Cells, Cultured, Colforsin, GTP-Binding Protein alpha Subunits, Gq-G11, GTP-Binding Protein alpha Subunits, Gs, Humans, Interleukin-4, Mast Cells, NFATC Transcription Factors, Receptor, Adenosine A2B, Signal Transduction, Up-Regulation
Show Abstract · Added December 10, 2013
Human mast cells express functional A(2A) and A(2B) adenosine receptors. However, only stimulation of A(2B), not A(2A), leads to secretion of interleukin (IL)-4, an important step in adenosine receptor-mediated induction of IgE synthesis by B-cells. In this study, we investigate intracellular pathways that link stimulation of A(2B) receptors to IL-4 up-regulation in HMC-1 mast cells. Both A(2A) and A(2B) receptors couple to G(s) proteins and stimulate adenylate cyclase, but only A(2B) stimulates phospholipase Cbeta through coupling to G(q) proteins leading to activation of protein kinase C and calcium mobilization. Inhibition of phospholipase Cbeta completely blocked A(2B) receptor-dependent IL-4 secretion. The protein kinase C inhibitor 2-{8-[(dimethylamino)-methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-3-yl}-3-(1-methyl-1H-indol-3-yl)maleimide (Ro-32-0432) had no effect on A(2B) receptor-mediated IL-4 secretion but inhibited phorbol 12-myristate 13-acetate-stimulated IL-4 secretion. In contrast, chelation of intracellular Ca(2+) inhibited both A(2B) receptor- and ionomycin-dependent IL-4 secretion. This Ca(2+)-sensitive pathway probably includes calcineurin and nuclear factor of activated T cells, because A(2B) receptor-dependent IL-4 secretion was blocked with cyclosporin A or 11R-VIVIT peptide. G(s)-linked pathways also play a role in the A(2B) receptor-dependent stimulation of IL-4 secretion; inhibition of adenylate cyclase or protein kinase A attenuated A(2B) receptor-dependent IL-4 secretion. Although stimulation of adenylate cyclase with forskolin did not increase IL-4 secretion on its own, it potentiated the effect of Pasteurella multocida toxin by 2-fold and ionomycin by 3-fold. Both forskolin and stimulation of A(2B) receptors up-regulated NFATc1 protein levels. We conclude that A(2B) receptors up-regulate IL-4 through G(q) signaling that is potentiated via cross-talk with G(s)-coupled pathways.
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12 MeSH Terms