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Toll-like receptor 3-mediated inflammation by p38 is enhanced by endothelial nitric oxide synthase knockdown.
Koch SR, Choi H, Mace EH, Stark RJ
(2019) Cell Commun Signal 17: 33
MeSH Terms: Capillary Permeability, Cells, Cultured, Chemokine CXCL10, Endothelium, Vascular, Gene Knockdown Techniques, Humans, Inflammation, Interleukin-6, Interleukin-8, Nitric Oxide Synthase Type III, Poly I-C, RNA, Small Interfering, Toll-Like Receptor 3, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added April 17, 2019
BACKGROUND - Vascular dysfunction is commonly seen during severe viral infections. Endothelial nitric oxide synthase (eNOS), has been postulated to play an important role in regulating vascular homeostasis as well as propagation of the inflammatory reaction. We hypothesized that the loss of eNOS would negatively impact toll-like receptor 3 (TLR3) signaling and worsen vascular function to viral challenge.
METHODS - Human microvascular endothelial cells (HMVECs) were exposed to either control or eNOS siRNA and then treated with Poly I:C, a TLR3 agonist and mimicker of dsRNA viruses. Cells were assessed for protein-protein associations, cytokine and chemokine analysis as well as transendothelial electrical resistance (TEER) as a surrogate of permeability.
RESULTS - HMVECs that had reduced eNOS expression had a significantly elevated increase in IL-6, IL-8 and IP-10 production after Poly I:C. In addition, the knockdown of eNOS enhanced the change in TEER after Poly I:C stimulation. Western blot analysis showed enhanced phosphorylation of p38 in sieNOS treated cells with Poly I:C compared to siControl cells. Proximity ligation assays further demonstrated direct eNOS-p38 protein-protein interactions. The addition of the p38 inhibitor, SB203580, in eNOS knockdown cells reduced both cytokine production after Poly I:C, and as well as mitigated the reduction in TEER, suggesting a direct link between eNOS and p38 in TLR3 signaling.
CONCLUSIONS - These results suggest that reduction of eNOS increases TLR3-mediated inflammation in human endothelial cells in a p38-dependent manner. This finding has important implications for understanding the pathogenesis of severe viral infections and the associated vascular dysfunction.
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14 MeSH Terms
Myeloid-Derived Suppressor Cells and Pulmonary Hypertension.
Bryant AJ, Mehrad B, Brusko TM, West JD, Moldawer LL
(2018) Int J Mol Sci 19:
MeSH Terms: Animals, Dendritic Cells, Humans, Hypertension, Pulmonary, Myeloid-Derived Suppressor Cells, Receptors, Interleukin-8B, Signal Transduction
Show Abstract · Added April 2, 2019
Myeloid⁻derived suppressor cells (MDSCs) comprised a heterogeneous subset of bone marrow⁻derived myeloid cells, best studied in cancer research, that are increasingly implicated in the pathogenesis of pulmonary vascular remodeling and the development of pulmonary hypertension. Stem cell transplantation represents one extreme interventional strategy for ablating the myeloid compartment but poses a number of translational challenges. There remains an outstanding need for additional therapeutic targets to impact MDSC function, including the potential to alter interactions with innate and adaptive immune subsets, or alternatively, alter trafficking receptors, metabolic pathways, and transcription factor signaling with readily available and safe drugs. In this review, we summarize the current literature on the role of myeloid cells in the development of pulmonary hypertension, first in pulmonary circulation changes associated with myelodysplastic syndromes, and then by examining intrinsic myeloid cell changes that contribute to disease progression in pulmonary hypertension. We then outline several tractable targets and pathways relevant to pulmonary hypertension via MDSC regulation. Identifying these MDSC-regulated effectors is part of an ongoing effort to impact the field of pulmonary hypertension research through identification of myeloid compartment-specific therapeutic applications in the treatment of pulmonary vasculopathies.
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MeSH Terms
Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells.
Chung L, Thiele Orberg E, Geis AL, Chan JL, Fu K, DeStefano Shields CE, Dejea CM, Fathi P, Chen J, Finard BB, Tam AJ, McAllister F, Fan H, Wu X, Ganguly S, Lebid A, Metz P, Van Meerbeke SW, Huso DL, Wick EC, Pardoll DM, Wan F, Wu S, Sears CL, Housseau F
(2018) Cell Host Microbe 23: 203-214.e5
MeSH Terms: Adenomatous Polyposis Coli Protein, Animals, Bacterial Toxins, Bacteroides fragilis, Carcinogenesis, Cell Line, Tumor, Colon, Colorectal Neoplasms, Enzyme Activation, Epithelial Cells, Female, Gene Deletion, HT29 Cells, Humans, Inflammation, Interleukin-17, Male, Metalloendopeptidases, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells, Receptors, Interleukin-17, Receptors, Interleukin-8B, STAT3 Transcription Factor, Transcription Factor RelA
Show Abstract · Added March 20, 2018
Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using Apc mice colonized with the human pathobiont enterotoxigenic Bacteroides fragilis (ETBF) as a model of microbe-induced colon tumorigenesis, we show that the Bacteroides fragilis toxin (BFT) triggers a pro-carcinogenic, multi-step inflammatory cascade requiring IL-17R, NF-κB, and Stat3 signaling in colonic epithelial cells (CECs). Although necessary, Stat3 activation in CECs is not sufficient to trigger ETBF colon tumorigenesis. Notably, IL-17-dependent NF-κB activation in CECs induces a proximal to distal mucosal gradient of C-X-C chemokines, including CXCL1, that mediates the recruitment of CXCR2-expressing polymorphonuclear immature myeloid cells with parallel onset of ETBF-mediated distal colon tumorigenesis. Thus, BFT induces a pro-carcinogenic signaling relay from the CEC to a mucosal Th17 response that results in selective NF-κB activation in distal colon CECs, which collectively triggers myeloid-cell-dependent distal colon tumorigenesis.
Copyright © 2018 Elsevier Inc. All rights reserved.
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26 MeSH Terms
The role of MyD88- and TRIF-dependent signaling in monophosphoryl lipid A-induced expansion and recruitment of innate immunocytes.
Hernandez A, Bohannon JK, Luan L, Fensterheim BA, Guo Y, Patil NK, McAdams C, Wang J, Sherwood ER
(2016) J Leukoc Biol 100: 1311-1322
MeSH Terms: Adaptor Proteins, Vesicular Transport, Animals, CD11b Antigen, Chemokine CXCL1, Chemokine CXCL2, Chemotaxis, Leukocyte, Granulocyte Colony-Stimulating Factor, Immunity, Innate, L-Selectin, Lipid A, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Monocytes, Myeloid Differentiation Factor 88, Myelopoiesis, Neutrophils, Receptors, Interleukin-8B, Signal Transduction, Toll-Like Receptor 4
Show Abstract · Added December 13, 2016
Treatment with the TLR4 agonist MPLA augments innate resistance to common bacterial pathogens. However, the cellular and molecular mechanisms by which MPLA augments innate immunocyte functions are not well characterized. This study examined the importance of MyD88- and TRIF-dependent signaling for leukocyte mobilization, recruitment, and activation following administration of MPLA. MPLA potently induced MyD88- and TRIF-dependent signaling. A single injection of MPLA caused rapid mobilization and recruitment of neutrophils, a response that was largely mediated by the chemokines CXCL1 and -2 and the hemopoietic factor G-CSF. Rapid neutrophil recruitment and chemokine production were regulated by both pathways although the MyD88-dependent pathway showed some predominance. In further studies, multiple injections of MPLA potently induced mobilization and recruitment of neutrophils and monocytes. Neutrophil recruitment after multiple injections of MPLA was reliant on MyD88-dependent signaling, but effective monocyte recruitment required activation of both pathways. MPLA treatment induced expansion of myeloid progenitors in bone marrow and upregulation of CD11b and shedding of L-selectin by neutrophils, all of which were attenuated in MyD88- and TRIF-deficient mice. These results show that MPLA-induced neutrophil and monocyte recruitment, expansion of bone marrow progenitors and augmentation of neutrophil adhesion molecule expression are regulated by both the MyD88- and TRIF-dependent pathways.
© Society for Leukocyte Biology.
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21 MeSH Terms
IL-17a and IL-22 Induce Expression of Antimicrobials in Gastrointestinal Epithelial Cells and May Contribute to Epithelial Cell Defense against Helicobacter pylori.
Dixon BR, Radin JN, Piazuelo MB, Contreras DC, Algood HM
(2016) PLoS One 11: e0148514
MeSH Terms: Animals, Anti-Infective Agents, CD4-Positive T-Lymphocytes, Epithelial Cells, Epithelium, Gastritis, Gastrointestinal Tract, Helicobacter Infections, Helicobacter pylori, Humans, Inflammation, Interleukin-17, Interleukin-8, Interleukins, Leukocyte L1 Antigen Complex, Lipocalins, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Real-Time Polymerase Chain Reaction, Stomach
Show Abstract · Added April 28, 2016
Helicobacter pylori colonization of the human stomach can lead to adverse clinical outcomes including gastritis, peptic ulcers, or gastric cancer. Current data suggest that in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization. Specifically, CD4+ T cell responses impact the pathology elicited in response to H. pylori. Because gastritis is believed to be the initiating host response to more detrimental pathological outcomes, there has been a significant interest in pro-inflammatory T cell cytokines, including the cytokines produced by T helper 17 cells. Th17 cells produce IL-17A, IL-17F, IL-21 and IL-22. While these cytokines have been linked to inflammation, IL-17A and IL-22 are also associated with anti-microbial responses and control of bacterial colonization. The goal of this research was to determine the role of IL-22 in activation of antimicrobial responses in models of H. pylori infection using human gastric epithelial cell lines and the mouse model of H. pylori infection. Our data indicate that IL-17A and IL-22 work synergistically to induce antimicrobials and chemokines such as IL-8, components of calprotectin (CP), lipocalin (LCN) and some β-defensins in both human and primary mouse gastric epithelial cells (GEC) and gastroids. Moreover, IL-22 and IL-17A-activated GECs were capable of inhibiting growth of H. pylori in vitro. While antimicrobials were activated by IL-17A and IL-22 in vitro, using a mouse model of H. pylori infection, the data herein indicate that IL-22 deficiency alone does not render mice more susceptible to infection, change their antimicrobial gene transcription, or significantly change their inflammatory response.
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22 MeSH Terms
Helicobacter pylori virulence factors affecting gastric proton pump expression and acid secretion.
Hammond CE, Beeson C, Suarez G, Peek RM, Backert S, Smolka AJ
(2015) Am J Physiol Gastrointest Liver Physiol 309: G193-201
MeSH Terms: Achlorhydria, Antigens, Bacterial, Bacterial Proteins, Cells, Cultured, Epithelial Cells, Gastric Acid, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Interleukin-8, NF-kappa B, Promoter Regions, Genetic, Proton Pumps, Signal Transduction, Sodium-Potassium-Exchanging ATPase, Virulence Factors
Show Abstract · Added February 5, 2016
Acute Helicobacter pylori infection of gastric epithelial cells and human gastric biopsies represses H,K-ATPase α subunit (HKα) gene expression and inhibits acid secretion, causing transient hypochlorhydria and supporting gastric H. pylori colonization. Infection by H. pylori strains deficient in the cag pathogenicity island (cag PAI) genes cagL, cagE, or cagM, which do not transfer CagA into host cells or induce interleukin-8 secretion, does not inhibit HKα expression, nor does a cagA-deficient strain that induces IL-8. To test the hypothesis that virulence factors other than those mediating CagA translocation or IL-8 induction participate in HKα repression by activating NF-κB, AGS cells transfected with HKα promoter-Luc reporter constructs containing an intact or mutated NF-κB binding site were infected with wild-type H. pylori strain 7.13, isogenic mutants lacking cag PAI genes responsible for CagA translocation and/or IL-8 induction (cagA, cagζ, cagε, cagZ, and cagβ), or deficient in genes encoding two peptidoglycan hydrolases (slt and cagγ). H. pylori-induced AGS cell HKα promoter activities, translocated CagA, and IL-8 secretion were measured by luminometry, immunoblotting, and ELISA, respectively. Human gastric biopsy acid secretion was measured by microphysiometry. Taken together, the data showed that HKα repression is independent of IL-8 expression, and that CagA translocation together with H. pylori transglycosylases encoded by slt and cagγ participate in NF-κB-dependent HKα repression and acid inhibition. The findings are significant because H. pylori factors other than CagA and IL-8 secretion are now implicated in transient hypochlorhydria which facilitates gastric colonization and potential triggering of epithelial progression to neoplasia.
Copyright © 2015 the American Physiological Society.
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17 MeSH Terms
Regulation of Helicobacter pylori Virulence Within the Context of Iron Deficiency.
Noto JM, Lee JY, Gaddy JA, Cover TL, Amieva MR, Peek RM
(2015) J Infect Dis 211: 1790-4
MeSH Terms: Animals, Antigens, Bacterial, Bacterial Proteins, Gene Knockout Techniques, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Interleukin-8, Iron, Stomach, Virulence
Show Abstract · Added January 20, 2015
Helicobacter pylori strains that harbor the oncoprotein CagA increase gastric cancer risk, and this risk is augmented under iron-deficient conditions. We demonstrate here that iron depletion induces coccoid morphology in strains lacking cagA. To evaluate the stability of augmented H. pylori virulence phenotypes stimulated by low-iron conditions, H. pylori isolated from iron-depleted conditions in vivo were serially passaged in vitro. Long-term passage decreased the ability of hypervirulent strains to translocate CagA or induce interleukin 8, indicating that hypervirulent phenotypes stimulated by low-level iron conditions are reversible. Therefore, rectifying iron deficiency may attenuate disease among H. pylori-infected persons with no response to antibiotics.
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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11 MeSH Terms
Validation of a multiplex electrochemiluminescent immunoassay platform in human and mouse samples.
Bastarache JA, Koyama T, Wickersham NE, Ware LB
(2014) J Immunol Methods 408: 13-23
MeSH Terms: Animals, Biomarkers, Bronchoalveolar Lavage Fluid, Electrochemical Techniques, Enzyme-Linked Immunosorbent Assay, Humans, Inflammation Mediators, Interleukin-6, Interleukin-8, Interleukins, Limit of Detection, Luminescent Measurements, Mice, Mice, Inbred C57BL, Predictive Value of Tests, Reagent Kits, Diagnostic, Reproducibility of Results, Species Specificity
Show Abstract · Added May 19, 2014
BACKGROUND - Despite the widespread use of multiplex immunoassays, there are very few scientific reports that test the accuracy and reliability of a platform prior to publication of experimental data. Our laboratory has previously demonstrated the need for new assay platform validation prior to use of biologic samples from large studies in order to optimize sample handling and assay performance.
METHODS - In this study, our goal was to test the accuracy and reproducibility of an electrochemiluminescent multiplex immunoassay platform (Meso Scale Discovery, MSD®) and compare this platform to validated, singleplex immunoassays (R&D Systems®) using actual study subject (human plasma and mouse bronchoalveolar lavage fluid (BAL) and plasma) samples.
RESULTS - We found that the MSD platform performed well on intra- and inter-assay comparisons, spike and recovery and cross-platform comparisons. The mean intra-assay CV% and range for MSD were 3.49 (0.0-10.4) for IL-6 and 2.04 (0.1-7.9) for IL-8. The correlation between values for identical samples measured on both MSD and R&D was R=0.97 for both analytes. The mouse MSD assay had a broader range of CV% with means ranging from 9.5 to 28.5 depending on the analyte. The range of mean CV% was similar for single plex ELISAs at 4.3-23.7 depending on the analyte. Regardless of species or sample type, CV% was more variable at lower protein concentrations.
CONCLUSIONS - In conclusion, we validated a multiplex electrochemiluminescent assay system and found that it has superior test characteristics in human plasma compared to mouse BALF and plasma. Both human and MSD assays compared favorably to well-validated singleplex ELISAs.
Published by Elsevier B.V.
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18 MeSH Terms
Adaptor protein2 (AP2) orchestrates CXCR2-mediated cell migration.
Raman D, Sai J, Hawkins O, Richmond A
(2014) Traffic 15: 451-69
MeSH Terms: Adaptor Protein Complex 2, Base Sequence, Chemotaxis, DNA Primers, Endocytosis, HEK293 Cells, HL-60 Cells, Humans, Mutagenesis, Site-Directed, Receptors, Interleukin-8B
Show Abstract · Added January 30, 2014
The chemokine receptor CXCR2 is vital for inflammation, wound healing, angiogenesis, cancer progression and metastasis. Adaptor protein 2 (AP2), a clathrin binding heterotetrameric protein comprised of α, β2, μ2 and σ2 subunits, facilitates clathrin-mediated endocytosis. Mutation of the LLKIL motif in the CXCR2 carboxyl-terminal domain (CTD) results in loss of AP2 binding to the receptor and loss of ligand-mediated receptor internalization and chemotaxis. AP2 knockdown also results in diminished ligand-mediated CXCR2 internalization, polarization and chemotaxis. Using knockdown/rescue approaches with AP2-μ2 mutants, the binding domains were characterized in reference to CXCR2 internalization and chemotaxis. When in an open conformation, μ2 Patch 1 and Patch 2 domains bind tightly to membrane PIP2 phospholipids. When AP2-μ2, is replaced with μ2 mutated in Patch 1 and/or Patch 2 domains, ligand-mediated receptor binding and internalization are not lost. However, chemotaxis requires AP2-μ2 Patch 1, but not Patch 2. AP2-σ2 has been demonstrated to bind dileucine motifs to facilitate internalization. Expression of AP2-σ2 V88D and V98S dominant negative mutants resulted in loss of CXCR2 mediated chemotaxis. Thus, AP2 binding to both membrane phosphatidylinositol phospholipids and dileucine motifs is crucial for directional migration or chemotaxis. Moreover, AP2-mediated receptor internalization can be dissociated from AP2-mediated chemotaxis.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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10 MeSH Terms
Association of soy food intake with risk and biomarkers of coronary heart disease in Chinese men.
Yu D, Zhang X, Xiang YB, Yang G, Li H, Fazio S, Linton M, Cai Q, Zheng W, Gao YT, Shu XO
(2014) Int J Cardiol 172: e285-7
MeSH Terms: Adult, Aged, Asian Continental Ancestry Group, Biomarkers, Cohort Studies, Coronary Disease, Cross-Sectional Studies, Eating, Follow-Up Studies, Humans, Interleukin-8, Male, Middle Aged, Plasminogen Activator Inhibitor 1, Prospective Studies, Risk Factors, Soy Foods
Added March 18, 2014
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17 MeSH Terms