bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cutting Edge: A Common Polymorphism Impairs Cell Surface Trafficking and Functional Responses of TLR1 but Protects against Leprosy
Authors: Johnson Christopher M. , Lyle Elizabeth A. , Omueti Katherine O. , Stepensky Vitaly A. , Yegin Olcay , Alpsoy Erkan , Hamann Lutz , Schumann Ralf R. , Tapping Richard I. 
Published: April 2014

Abstract
TLRs constitute an essential family of pattern recognition molecules that, through direct recognition of conserved microbial components, initiate inflammatory responses following infection. In this role, TLR1 enables host responses to a variety of bacteria, including pathogenic species of mycobacteria. In this study, we report that I602S, a common single nucleotide polymorphism within TLR1, is associated with aberrant trafficking of the receptor to the cell surface and diminished responses of blood monocytes to bacterial agonists. When expressed in heterologous systems, the TLR1 602S variant, but not the TLR1 602I variant, exhibits the expected deficiencies in trafficking and responsiveness. Among white Europeans, the 602S allele represents the most common single nucleotide polymorphism affecting TLR function identified to date. Surprisingly, the 602S allele is associated with a decreased incidence of leprosy, suggesting that Mycobacterium leprae subverts the TLR system as a mechanism of immune evasion.
Impaired Accumulation of Antigen-Specific CD8 Lymphocytes in Chemokine CCL25-Deficient Intestinal Epithelium and Lamina Propria
Authors: Wurbel Marc-André , Malissen Marie , Guy-Grand Delphine , Malissen Bernard , Campbell James J. 
Published: April 2014

Abstract
CCL25 and CCR9 constitute a chemokine/receptor pair involved in T cell development and in gut-associated immune responses. In this study, we generated CCL25−/− mice to answer questions that could not be addressed with existing CCR9−/− mice. Similar phenotypes were observed for both CCL25−/− and CCR9−/− mice, consistent with the notion that CCL25 and CCR9 interact with each other exclusively. We assessed the requirement for CCL25 in generating CCR9high CD8 intestinal memory-phenotype T cells and the subsequent accumulation of these cells within effector sites. TCR-transgenic naive CD8 T cells were transferred into wild-type or CCL25-deficient hosts. Oral sensitization with Ag allowed these naive donor cells to efficiently differentiate into CCR9high memory-phenotype cells within the mesenteric lymph nodes of wild-type hosts. This differentiation event occurred with equal efficiency in the MLN of CCL25-deficient hosts, demonstrating that CCL25 is not required to induce the CCR9high memory phenotype in vivo. However, we found that CCL25 deficiency severely impaired the Ag-dependent accumulation of donor-derived CD8 T cells within both lamina propria and epithelium of the small intestine. Thus, although CCL25 is not necessary for generating memory-phenotype CD8 T cells with “gut-homing” properties, this chemokine is indispensable for their trafficking to the small intestine.
Krüppel-Like Factor 2 Controls T Cell Trafficking by Activating L-Selectin (CD62L) and Sphingosine-1-Phosphate Receptor 1 Transcription
Authors: Bai Ailin , Hu Hui , Yeung Mandy , Chen Jianzhu 
Published: April 2014

AbstractKrüppel-like factor 2 (KLF2) is a member of zinc-finger transcription factors. Based on its expression in naive and memory T cells and the activated phenotype of few T cells in mice lacking KLF2 in the lymphoid lineage, KLF2 is postulated to regulate T cell homeostasis by promoting cell quiescence. In this study, we show that in reporter gene assays KLF2 directly activates the promoters of both CD62L and sphingosine-1-phosphate receptor 1 (S1P1), whose expression is critical for T cell egress from the thymus and homing to the lymph nodes. Correspondingly, exogenous KLF2 expression in primary T cells significantly up-regulates both CD62L and S1P1. Following adoptive transfer, KLF2-transduced T cells are much more efficient in homing to lymphoid organs than nontransduced T cells. These findings suggest that KLF2 regulates T cell homeostasis at least partly by controlling CD62L and S1P1 expression, and therefore T cell egress from the thymus and circulation in the periphery.
Acute Alcohol Exposure Exerts Anti-Inflammatory Effects by Inhibiting IκB Kinase Activity and p65 Phosphorylation in Human Monocytes
Authors: Mandrekar Pranoti , Jeliazkova Valentina , Catalano Donna , Szabo Gyongyi 
Published: April 2014

Abstract
Acute alcohol use is associated with impaired immune responses and decreased proinflammatory cytokine production. Our earlier studies have shown that acute alcohol intake inhibits NF-κB DNA binding in an IκBα-independent manner. We report using human peripheral blood monocytes and Chinese hamster ovary cells transfected with CD14 cells that acute alcohol treatment in vitro exerts NF-κB inhibition by disrupting phosphorylation of p65. Immunoprecipitation of p65 and IκBα revealed that acute alcohol exposure for 1 h decreased NF-κB-IκBα complexes in the cytoplasm. Phosphorylation of p65 at Ser536 is mediated by IκB kinase (IKK)β and is required for NF-κB-dependent cellular responses. We show that acute alcohol treatment decreased LPS-induced IKKα and IKKβ activity resulting in decreased phosphorylation of p65 at Ser536. Furthermore, nuclear expression of IKKα increased after alcohol treatment, which may contribute to inhibition of NF-κB. Decreased phosphorylation of nuclear p65 at Ser276 was likely not due to alcohol-induced inhibition of protein kinase A and mitogen- and stress-activated protein kinase-1 activity. Although decreased IκBα phosphorylation after acute alcohol treatment was attributable to reduced IKKβ activity, degradation of IκBα during alcohol exposure was IKKβ-independent. Alcohol-induced degradation of IκBα in the presence of a 26S proteasome inhibitor suggested proteasome-independent IκBα degradation. Collectively, our studies suggest that acute alcohol exposure modulates IκBα-independent NF-κB activity primarily by affecting phosphorylation of p65. These findings further implicate an important role for IKKβ in the acute effects of alcohol in immune cells.
The Loss of Telomerase Activity in Highly Differentiated CD8+CD28−CD27− T Cells Is Associated with Decreased Akt (Ser473) Phosphorylation
Authors: Plunkett Fiona J. , Franzese Ornella , Finney Helene M. , Fletcher Jean M. , Belaramani Lavina L. , Salmon Mike , Dokal Inderjeet , Webster David , Lawson Alastair D. G. , Akbar Arne N. 
Published: April 2014

Abstract
The enzyme telomerase is essential for maintaining the replicative capacity of memory T cells. Although CD28 costimulatory signals can up-regulate telomerase activity, human CD8+ T cells lose CD28 expression after repeated activation. Nevertheless, telomerase is still inducible in CD8+CD28− T cells. To identify alternative costimulatory pathways that may be involved, we introduced chimeric receptors containing the signaling domains of CD28, CD27, CD137, CD134, and ICOS in series with the CD3 zeta (ζ) chain into primary human CD8+ T cells. Although CD3 ζ-chain signals alone were ineffective, triggering of all the other constructs induced proliferation and telomerase activity. However, not all CD8+CD28− T cells could up-regulate this enzyme. The further fractionation of CD8+CD28− T cells into CD8+CD28− CD27+ and CD8+CD28−CD27− subsets showed that the latter had significantly shorter telomeres and extremely poor telomerase activity. The restoration of CD28 signaling in CD8+CD28−CD27− T cells could not reverse the low telomerase activity that was not due to decreased expression of human telomerase reverse transcriptase, the enzyme catalytic subunit. Instead, the defect was associated with decreased phosphorylation of the kinase Akt, that phosphorylates human telomerase reverse transcriptase to induce telomerase activity. Furthermore, the defective Akt phosphorylation in these cells was specific for the Ser473 but not the Thr308 phosphorylation site of this molecule. Telomerase down-regulation in highly differentiated CD8+CD28−CD27− T cells marks their inexorable progress toward a replicative end stage after activation. This limits the ability of memory CD8+ T cells to be maintained by continuous proliferation in vivo.
Requirements for T Lymphocyte Migration in Explanted Lymph Nodes
Authors: Huang Julie H. , Cárdenas-Navia L. Isabel , Caldwell Charles C. , Plumb Troy J. , Radu Caius G. , Rocha Paulo N. , Wilder Tuere , Bromberg Jonathan S. , Cronstein Bruce N. , Sitkovsky Michail , Dewhirst Mark W. , Dustin Michael L. 
Published: April 2014

Abstract
Although the requirements for T lymphocyte homing to lymph nodes (LNs) are well studied, much less is known about the requirements for T lymphocyte locomotion within LNs. Imaging of murine T lymphocyte migration in explanted LNs using two-photon laser-scanning fluorescence microscopy provides an opportunity to systematically study these requirements. We have developed a closed system for imaging an intact LN with controlled temperature, oxygenation, and perfusion rate. Naive T lymphocyte locomotion in the deep paracortex of the LN required a perfusion rate of &gt;13 μm/s and a partial pressure of O2 (pO2) of &gt;7.4%. Naive T lymphocyte locomotion in the subcapsular region was 38% slower and had higher turning angles and arrest coefficients than naive T lymphocytes in the deep paracortex. T lymphocyte activation decreased the requirement for pO2, but also decreased the speed of locomotion in the deep paracortex. Although CCR7−/− naive T cells displayed a small reduction in locomotion, systemic treatment with pertussis toxin reduced naive T lymphocyte speed by 59%, indicating a contribution of Gαi-mediated signaling, but involvement of other G protein-coupled receptors besides CCR7. Receptor knockouts or pharmacological inhibition in the adenosine, PG/lipoxygenase, lysophosphatidylcholine, and sphingosine-1-phosphate pathways did not individually alter naive T cell migration. These data implicate pO2, tissue architecture, and G-protein coupled receptor signaling in regulation of naive T lymphocyte migration in explanted LNs.
Expression of the Voltage-Gated Sodium Channel NaV1.5 in the Macrophage Late Endosome Regulates Endosomal Acidification
Authors: Carrithers Michael D. , Dib-Hajj Sulayman , Carrithers Lisette M. , Tokmoulina Gouzel , Pypaert Marc , Jonas Elizabeth A. , Waxman Stephen G. 
Published: April 2014

Abstract
Voltage-gated sodium channels expressed on the plasma membrane activate rapidly in response to changes in membrane potential in cells with excitable membranes such as muscle and neurons. Macrophages also require rapid signaling mechanisms as the first line of defense against invasion by microorganisms. In this study, our goal was to examine the role of intracellular voltage-gated sodium channels in macrophage function. We demonstrate that the cardiac voltage-gated sodium channel, NaV1.5, is expressed on the late endosome, but not the plasma membrane, in a human monocytic cell line, THP-1, and primary human monocyte-derived macrophages. Although the neuronal channel, NaV1.6, is also expressed intracellularly, it has a distinct subcellular localization. In primed cells, NaV1.5 regulates phagocytosis and endosomal pH during LPS-mediated endosomal acidification. Activation of the endosomal channel causes sodium efflux and decreased intraendosomal pH. These results demonstrate a functionally relevant intracellular voltage-gated sodium channel and reveal a novel mechanism to regulate macrophage endosomal acidification.
The Nod-Like Receptor Family Member Naip5/Birc1e Restricts Legionella pneumophila Growth Independently of Caspase-1 Activation
Authors: Lamkanfi Mohamed , Amer Amal , Kanneganti Thirumala-Devi , Muñoz-Planillo Raúl , Chen Grace , Vandenabeele Peter , Fortier Anne , Gros Philippe , Núñez Gabriel 
Published: April 2014

Abstract
Similar to Ipaf and caspase-1, the Nod-like receptor protein Naip5 restricts intracellular proliferation of Legionella pneumophila, the causative agent of a severe form of pneumonia known as Legionnaires’ disease. Thus, Naip5 has been suggested to regulate Legionella replication inside macrophages through the activation of caspase-1. In this study, we show that cytosolic delivery of recombinant flagellin activated caspase-1 in A/J macrophages carrying a mutant Naip5 allele, and in C57BL/6 (B6) macrophages congenic for the mutant Naip5 allele (B6-Naip5A/J), but not in Ipaf−/− cells. In line with these results, A/J and B6-Naip5A/J macrophages induced high levels of caspase-1 activation and IL-1β secretion when infected with Legionella. In addition, transgenic expression of a functional Naip5 allele in A/J macrophages did not alter Legionella-induced caspase-1 activation and IL-1β secretion. Notably, defective Naip5 signaling renders B6-Naip5A/J macrophages permissive for Legionella proliferation despite normal caspase-1 activation. These results indicate that the restriction of intracellular Legionella replication is more complex than previously appreciated and requires both Ipaf-dependent caspase-1 activation as well as functional Naip5 signaling.
STAT1 Activation Causes Translocation of Bax to the Endoplasmic Reticulum during the Resolution of Airway Mucous Cell Hyperplasia by IFN-γ
Authors: Stout Barbara A. , Melendez Karla , Seagrave JeanClare , Holtzman Michael J. , Wilson Bridget , Xiang Jialing , Tesfaigzi Yohannes 
Published: April 2014

Abstract
Disruption of the normal resolution process of inflammation-induced mucous cell hyperplasia may lead to sustained mucous hypersecretion in chronic diseases. During prolonged exposure of mice to allergen, IFN-γ reduces mucous cell hyperplasia, but the signaling responsible for the cell death is largely unknown. A brief phosphorylation of STAT1 by IFN-γ was required for cell death in airway epithelial cells (AEC), and during prolonged exposure to allergen, mucous cell hyperplasia remained elevated in STAT1−/− but was resolved in STAT1+/+ mice. Although IFN-γ treatment of primary human AECs and other airway cell lines left Bax protein levels unchanged, it caused translocation of Bax from the cytosol to the endoplasmic reticulum (ER) but not to the mitochondria. Localization of Bax to the ER was observed in IFN-γ-treated primary AECs isolated from STAT1+/+ mice but not in cells from STAT1−/− mice. In addition, ER Bax was detected in mucous cells of STAT1+/+ but not STAT1−/− airways of mice exposed to allergen for prolonged periods. IFN-γ did not release cytochrome c from mitochondria but reduced ER calcium stores and dilated the ER, confirming that the IFN-γ-induced cell death is mediated through changes localized in the ER. Collectively, these observations suggest that STAT1-dependent translocation of Bax to the ER is crucial for IFN-γ-induced cell death of AECs and the resolution of allergen-induced mucous cell hyperplasia.
Oral Vaccination withSalmonellaSimultaneously ExpressingYersinia pestisF1 and V Antigens Protects against Bubonic and Pneumonic Plague
Authors: Yang Xinghong , Hinnebusch B. Joseph , Trunkle Theresa , Bosio Catharine M. , Suo Zhiyong , Tighe Mike , Harmsen Ann , Becker Todd , Crist Kathryn , Walters Nancy , Avci Recep , Pascual David W. 
Published: April 2014

AbstractThe gut provides a large area for immunization enabling the development of mucosal and systemic Ab responses. To test whether the protective Ags to Yersinia pestis can be orally delivered, the Y. pestis caf1 operon, encoding the F1-Ag and virulence Ag (V-Ag) were cloned into attenuated Salmonella vaccine vectors. F1-Ag expression was controlled under a promoter from the caf1 operon; two different promoters (P), PtetA in pV3, PphoP in pV4, as well as a chimera of the two in pV55 were tested. F1-Ag was amply expressed; the chimera in the pV55 showed the best V-Ag expression. Oral immunization with Salmonella-F1 elicited elevated secretory (S)-IgA and serum IgG titers, and Salmonella-V-Ag(pV55) elicited much greater S-IgA and serum IgG Ab titers than Salmonella-V-Ag(pV3) or Salmonella-V-Ag(pV4). Hence, a new Salmonella vaccine, Salmonella-(F1+V)Ags, made with a single plasmid containing the caf1 operon and the chimeric promoter for V-Ag allowed the simultaneous expression of F1 capsule and V-Ag. Salmonella-(F1+V)Ags elicited elevated Ab titers similar to their monotypic derivatives. For bubonic plague, mice dosed with Salmonella-(F1+V)Ags and Salmonella-F1-Ag showed similar efficacy (&gt;83% survival) against ∼1000 LD50 Y. pestis. For pneumonic plague, immunized mice required immunity to both F1- and V-Ags because the mice vaccinated with Salmonella-(F1+V)Ags protected against 100 LD50 Y. pestis. These results show that a single Salmonella vaccine can deliver both F1- and V-Ags to effect both systemic and mucosal immune protection against Y. pestis.
Identification of Genes Selectively Regulated by IFNs in Endothelial Cells
Authors: Indraccolo Stefano , Pfeffer Ulrich , Minuzzo Sonia , Esposito Giovanni , Roni Valeria , Mandruzzato Susanna , Ferrari Nicoletta , Anfosso Luca , Dell’Eva Raffaella , Noonan Douglas M. , Chieco-Bianchi Luigi , Albini Adriana , Amadori Alberto 
Published: April 2014

Abstract
IFNs are highly pleiotropic cytokines also endowed with marked antiangiogenic activity. In this study, the mRNA expression profiles of endothelial cells (EC) exposed in vitro to IFN-α, IFN-β, or IFN-γ were determined. We found that in HUVEC as well as in other EC types 175 genes were up-regulated (&gt;2-fold increase) by IFNs, including genes involved in the host response to RNA viruses, inflammation, and apoptosis. Interestingly, 41 genes showed a &gt;5-fold higher induction by IFN-α in EC compared with human fibroblasts; among them, the gene encoding the angiostatic chemokine CXCL11 was selectively induced by IFN-α in EC along with other genes associated with angiogenesis regulation, including CXCL10, TRAIL, and guanylate-binding protein 1. These transcriptional changes were confirmed and extended by quantitative PCR analysis and ELISA; whereas IFN-α and IFN-β exerted virtually identical effects on transcriptome modulation, a differential gene regulation by type I and type II IFN emerged, especially as far as quantitative aspects were concerned. In vivo, IFN-α-producing tumors overexpressed murine CXCL10 and CXCL11, guanylate-binding protein 1, and TRAIL, with evidence of CXCL11 production by tumor-associated EC. Overall, these findings improve our understanding of the antiangiogenic effects of IFNs by showing that these cytokines trigger an antiangiogenic transcriptional program in EC. Moreover, we suggest that quantitative differences in the magnitude of the transcriptional activation of IFN-responsive genes could form the basis for cell-specific transcriptional signatures.
Arachidonic Acid Metabolism as a Potential Mediator of Cardiac Fibrosis Associated with Inflammation
Authors: Levick Scott P. , Loch David C. , Taylor Stephen M. , Janicki Joseph S. 
Published: April 2014

Abstract
An increase in left ventricular collagen (cardiac fibrosis) is a detrimental process that adversely affects heart function. Strong evidence implicates the infiltration of inflammatory cells as a critical part of the process resulting in cardiac fibrosis. Inflammatory cells are capable of releasing arachidonic acid, which may be further metabolized by cyclooxygenase, lipoxygenase, and cytochrome P450 monooxygenase enzymes to biologically active products, including PGs, leukotrienes, epoxyeicosatrienoic acids, and hydroxyeicosatetraenoic acids. Some of these products have profibrotic properties and may represent a pathway by which inflammatory cells initiate and mediate the development of cardiac fibrosis. In this study, we critically review the current literature on the potential link between this pathway and cardiac fibrosis.
The Extra Domain A from Fibronectin Targets Antigens to TLR4-Expressing Cells and Induces Cytotoxic T Cell Responses In Vivo
Authors: Lasarte Juan J. , Casares Noelia , Gorraiz Marta , Hervás-Stubbs Sandra , Arribillaga Laura , Mansilla Cristina , Durantez Maika , Llopiz Diana , Sarobe Pablo , Borrás-Cuesta Francisco , Prieto Jesús , Leclerc Claude 
Published: April 2014

AbstractVaccination strategies based on the in vivo targeting of Ags to dendritic cells (DCs) are needed to improve the induction of specific T cell immunity against tumors and infectious agents. In this study, we have used a recombinant protein encompassing the extra domain A from fibronectin (EDA), an endogenous ligand for TLR4, to deliver Ags to TLR4-expressing DC. The purified EDA protein was shown to bind to TLR4-expressing HEK293 cells and to activate the TLR4 signaling pathway. EDA also stimulated the production by DC of proinflammatory cytokines such as IL-12 or TNF-α and induced their maturation in vitro and in vivo. A fusion protein between EDA and a cytotoxic T cell epitope from OVA efficiently presented this epitope to specific T cells and induced the in vivo activation of a strong and specific CTL response. Moreover, a fusion protein containing EDA and the full OVA also improved OVA presentation by DC and induced CTL responses in vivo. These EDA recombinant proteins protected mice from a challenge with tumor cells expressing OVA. These results strongly suggest that the fibronectin extra domain A may serve as a suitable Ag carrier for the development of antiviral or antitumoral vaccines.
Dual Assemblies of an Activating Immune Receptor, MAIR-II, with ITAM-Bearing Adapters DAP12 and FcRγ Chain on Peritoneal Macrophages
Authors: Nakahashi Chigusa , Tahara-Hanaoka Satoko , Totsuka Naoya , Okoshi Yasushi , Takai Toshiyuki , Ohkohchi Nobuhiro , Honda Shin-ichiro , Shibuya Kazuko , Shibuya Akira 
Published: April 2014

Abstract
Certain activating immune receptors expressed on myeloid cells noncovalently associate with either DAP12 or FcεRIγ (FcRγ chain), the ITAM-bearing transmembrane adapter proteins. An activating receptor, myeloid-associated Ig-like receptor (MAIR) II, is expressed on a subset of B cells and macrophages in the spleen and peritoneal cavity of mice and associates with DAP12 in these cells. However, we demonstrate here that cross-linking MAIR-II with mAb induced secretion of a significant amount of the inflammatory cytokines TNF-α and IL-6 from DAP12−/− as well as wild-type (WT) peritoneal macrophages. We show that MAIR-II associates with not only DAP12 but also FcRγ chain homodimers in peritoneal macrophages. LPS enhanced the FcRγ chain expression and FcRγ chain-dependent cell surface expression of MAIR-II and had additive effects on MAIR-II-mediated inflammatory cytokine secretion from peritoneal macrophages. The lysine residue in the transmembrane region of MAIR-II was involved in the association with FcRγ chain as well as DAP12. Our findings present the first case of an activating receptor that uses either DAP12 or FcRγ chain as a signaling adapter. The FcRγ chain may provide cooperation with and/or compensation for DAP12 in MAIR-II-mediated inflammatory responses by peritoneal macrophages.