bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Short-Form C-Type Lectin from Amphioxus Acts as a Direct Microbial Killing Protein via Interaction with Peptidoglycan and Glucan
Authors: Yu Yanhong , Yu Yingcai , Huang Huiqing , Feng Kaixia , Pan Minming , Yuan Shaochun , Huang Shengfeng , Wu Tao , Guo Lei , Dong Meiling , Chen Shangwu , Xu Anlong 
Published: April 2014

Abstract
To investigate the evolution and immune function of C-type lectin in amphioxus, the primitive representative of the chordate phylum, we identified three C-type lectins consisting solely of a carbohydrate recognition domain and N-terminal signal peptide and found that they had distinct express patterns in special tissues and immune response to stimulations analyzed by quantitative real-time PCR. We characterized the biochemical and biological properties of AmphiCTL1, which was dramatically up-regulated in amphioxus challenged with Staphylococcus aureus, Saccharomyces cerevisiae, and zymosan. Immunohistochemistry demonstrated that the localization of AmphiCTL1 protein was exclusively detected in the inner folding tissues of the hepatic diverticulum. Recombinant AmphiCTL1 was characterized as a typical Ca2+-dependent carbohydrate-binding protein possessing hemagglutinating activity, preferentially bound to all examined four Gram-positive bacteria and two yeast strains, but had little binding activity toward four Gram-negative bacteria we tested. It aggregated S. aureus and S. cerevisiae in a Ca2+-dependent manner and specifically bound to insoluble peptidoglycan and glucan, but not to LPS, lipoteichoic acid, and mannan. Calcium increased the intensity of the interaction between AmphiCTL1 and those components, but was not essential. This lectin directly killed S. aureus and S. cerevisiae in a Ca2+-independent fashion, and its binding to microorganism cell wall polysaccharides such as peptidoglycan and glucan preceded microbial killing activity. These findings suggested that AmphiCTL1 acted as a direct microbial killing C-type lectin through binding microbial targets via interaction with peptidoglycan and glucan. Thus, AmphiCTL1 may be an evolutionarily primitive form of antimicrobial protein involved in lectin-mediated innate immunity.
Candida albicans Triggers Activation of Distinct Signaling Pathways to Establish a Proinflammatory Gene Expression Program in Primary Human Endothelial Cells
Authors: Müller Verena , Viemann Dorothee , Schmidt Marc , Endres Nicole , Ludwig Stephan , Leverkus Martin , Roth Johannes , Goebeler Matthias 
Published: April 2014

Abstract
Endothelial cells (EC) actively participate in the innate defense against microbial pathogens. Under unfavorable conditions, defense reactions can turn life threatening resulting in sepsis. We therefore studied the so far largely unknown EC reaction patterns to the fungal pathogen Candida albicans, which is a major cause of lethality in septic patients. Using oligonucleotide microarray analysis, we identified 56 genes that were transcriptionally up-regulated and 69 genes that were suppressed upon exposure of ECs to C. albicans. The most significantly up-regulated transcripts were found in gene ontology groups comprising the following categories: chemotaxis/migration; cell death and proliferation; signaling; transcriptional regulation; and cell-cell contacts/intercellular signaling. Further examination of candidate signaling cascades established a central role of the proinflammatory NF-κB pathway in the regulation of the Candida-modulated transcriptome of ECs. As a second major regulatory pathway we identified the stress-activated p38 MAPK pathway, which critically contributes to the regulation of selected Candida target genes such as CXCL8/IL-8. Depletion of MyD88 and IL-1R-associated kinase-1 by RNA interference demonstrates that Candida-induced NF-κB activation is mediated by pattern recognition receptor signaling. Additional experiments suggest that C. albicans-induced CXCL8/IL-8 expression is mediated by TLR3 rather than TLR2 and TLR4, which previously have been implicated with MyD88/IκB kinase-2/NF-κB activation by this fungus in other systems. Our study provides the first comprehensive analysis of endothelial gene responses to C. albicans and presents novel insights into the complex signaling patterns triggered by this important pathogen.
CD66b Regulates Adhesion and Activation of Human Eosinophils
Authors: Yoon Juhan , Terada Akihiko , Kita Hirohito 
Published: April 2014

Abstract
Eosinophils and their products are likely important in the pathophysiology of allergic diseases, such as bronchial asthma, and in host immunity to parasitic organisms. However, the mechanisms for proinflammatory mediator release by eosinophils are poorly understood. CD66b (CEACAM8, CGM6, NCA-95) is a single chain, GPI-anchored, highly glycosylated protein belonging to the carcinoembryonic Ag supergene family. CD66b is an activation marker for human granulocytes; however, its biological functions are largely unknown in eosinophils. We found that CD66b is highly expressed on the surface of human peripheral blood eosinophils isolated from healthy individuals. Engagement of CD66b, but not CD66a, by mAb or a natural ligand, galectin-3, activated a Src kinase family molecule, hemopoietic cell kinase (Hck), and induced cellular adhesion, superoxide production, and degranulation of eosinophils. CD66b molecules were localized in lipid rafts, and disruption of lipid rafts or removal of the GPI anchor inhibited the adhesion and activation of eosinophils. Importantly, CD66b was constitutively and physically associated with a β2 integrin, CD11b, and cross-linking of CD66b induced a striking clustering of CD11b molecules. Thus, CD66b molecules are involved in regulating adhesion and activation of eosinophils, possibly through their localization in lipid rafts and interaction with other cell surface molecules, such as CD11b. Binding of exogenous or endogenous carbohydrate ligands(s) to CD66b may be important in the release of proinflammatory mediators by human eosinophils.
E- and P-Selectin Are Not Required for the Development of Experimental Autoimmune Encephalomyelitis in C57BL/6 and SJL Mice
Authors: Döring Axinia , Wild Martin , Vestweber Dietmar , Deutsch Urban , Engelhardt Britta 
Published: April 2014

AbstractIn multiple sclerosis and in its animal model experimental autoimmune encephalomyelitis (EAE), inflammatory cells migrate across the endothelial blood-brain barrier (BBB) and gain access to the CNS. It is well-established that α4 integrins are actively involved in leukocyte recruitment across the BBB during EAE. In contrast, the role of endothelial E- and P-selectin in this process has been a controversial issue. In this study, we demonstrate that P-selectin protein can be detected in meningeal blood vessel endothelial cells in healthy SJL and C57BL/6 mice and on rare parenchymal CNS blood vessels in C57BL/6, but not SJL, mice. During EAE, expression of P-selectin but not E-selectin was found up-regulated on inflamed CNS microvessels surrounded by inflammatory infiltrates irrespective of their meningeal or parenchymal localization with a more prominent immunostaining detected in C57BL/6 as compared with SJL mice. P-selectin immunostaining could be localized to CNS endothelial cells and to CD41-positive platelets adhering to the vessel wall. Despite the presence of P-selectin in wild-type mice, E/P-selectin-deficient SJL and C57BL/6 mice developed clinical EAE indistinguishable from wild-type mice. Absence of E- and P-selectin did neither influence the activation of myelin-specific T cells nor the composition of the cellular infiltrates in the CNS during EAE. Finally, endothelial-specific tetracycline-inducible expression of E-selectin at the BBB in transgenic C57BL/6 mice did not alter the development of EAE. Thus, E- and P-selectin are not required for leukocyte recruitment across the BBB and the development of EAE in C57BL/6 and in SJL mice.
Caspase-4 Interacts with TNF Receptor-Associated Factor 6 and Mediates Lipopolysaccharide-Induced NF-κB-Dependent Production of IL-8 and CC Chemokine Ligand 4 (Macrophage-Inflammatory Protein-1β)
Authors: Lakshmanan Umayal , Porter Alan G. 
Published: April 2014

Abstract
Human caspase-4 does not have a corresponding mouse ortholog. Caspase-4 falls within the class of “inflammatory caspases,” being homologous with human caspases 1 and 5 and mouse caspases 1, 11, and 12. To address the function of caspase-4, we generated caspase-4-deficient human THP1 monocytic cell lines which exhibited substantially reduced LPS-induced secretion of several chemokines and cytokines, including IL-8 (CXCL8), CCL4 (macrophage-inflammatory protein-1β), CCL20 (macrophage-inflammatory protein-3α), and IL-1β. The LPS-induced expression of the mRNAs encoding these cytokines was correspondingly reduced in the caspase-4-deficient clones. Because a specific NF-κB inhibitor blocked LPS-induced IL-8 and CCL4 mRNA expression as well as IL-8 and CCL4 secretion in THP1 cells, we investigated the role of caspase-4 in NF-κB signaling. LPS-induced NF-κB nuclear translocation and activation were inhibited in all caspase-4-deficient clones. LPS stimulation led to the interaction of endogenous caspase-4 and TNFR-associated factor 6 (TRAF6) via a TRAF6-binding motif (PPESGE), which we identified in caspase-4. Mutation of this site in caspase-4 resulted in the loss of the TRAF6-caspase-4 interaction. Similar TRAF6-binding motifs are known to be functionally important for TRAF6 interactions with other molecules including caspase-8, and for mediating NF-κB activation in various immune and nonimmune cell types. Our data suggest that the TRAF6-caspase-4 interaction, triggered by LPS, leads to NF-κB-dependent transcriptional up-regulation and secretion of important cytokines and chemokines in innate immune signaling in human monocytic cells.
Pulmonary and Systemic Endotoxin Tolerance in Preterm Fetal Sheep Exposed to Chorioamnionitis
Authors: Kallapur Suhas G. , Jobe Alan H. , Ball Molly K. , Nitsos Ilias , Moss Timothy J. M. , Hillman Noah H. , Newnham John P. , Kramer Boris W. 
Published: April 2014

Abstract
In a model of human chorioamnionitis, fetal sheep exposed to a single injection, but not repeated injections, of intra-amniotic endotoxin develop lung injury responses. We hypothesized that repeated exposure to intra-amniotic endotoxin induces endotoxin tolerance. Fetal sheep were given intra-amniotic injections of saline (control) or Escherichia coli LPS O55:B5 (10 mg) either 2 days (2-day group, single exposure), 7 days (7-day group, single exposure), or 2 plus 7 days (2- and 7-day repeat exposure) before preterm delivery at 124 days gestation (term = 150 days). Endotoxin responses were assessed in vivo in the lung and liver, and in vitro in monocytes from the blood and the lung. Compared with the single 2-day LPS exposure group, the (2 plus 7 days) repeat LPS-exposed lambs had: 1) decreased lung neutrophil and monocyte inducible NO synthase (NOSII) expression, and 2) decreased lung cytokine and liver serum amyloid A3 mRNA expression. In the lung, serum amyloid A3 mRNA expression decreased in the airway epithelial cells but not in the lung inflammatory cells. Unlike the single 7-day LPS exposure group, peripheral blood and lung monocytes from the repeat-LPS group did not increase IL-6 secretion or hydrogen peroxide production in response to in vitro LPS. Compared with controls, TLR4 expression did not change but IL-1R-associated kinase M expression increased in the monocytes from repeat LPS-exposed lambs. These results are consistent with the novel finding of endotoxin tolerance in preterm fetal lungs exposed to intra-amniotic LPS. The findings have implications for preterm infants exposed to chorioamnionitis for both responses to lung injury and postnatal nosocomial infections.
Monocyte Chemoattractant Protein-1/CC Chemokine Ligand 2 Controls Microtubule-Driven Biogenesis and Leukotriene B4-Synthesizing Function of Macrophage Lipid Bodies Elicited by Innate Immune Response
Authors: Pacheco Patricia , Vieira-de-Abreu Adriana , Gomes Rachel N. , Barbosa-Lima Giselle , Wermelinger Leticia B. , Maya-Monteiro Clarissa M. , Silva Adriana R. , Bozza Marcelo T. , Castro-Faria-Neto Hugo C. , Bandeira-Melo Christianne , Bozza Patricia T. 
Published: April 2014

Abstract
Lipid bodies (also known as lipid droplets) are emerging as inflammatory organelles with roles in the innate immune response to infections and inflammatory processes. In this study, we identified MCP-1 as a key endogenous mediator of lipid body biogenesis in infection-driven inflammatory disorders and we described the cellular mechanisms and signaling pathways involved in the ability of MCP-1 to regulate the biogenesis and leukotriene B4 (LTB4) synthetic function of lipid bodies. In vivo assays in MCP-1−/− mice revealed that endogenous MCP-1 produced during polymicrobial infection or LPS-driven inflammatory responses has a critical role on the activation of lipid body-assembling machinery, as well as on empowering enzymatically these newly formed lipid bodies with LTB4 synthetic function within macrophages. MCP-1 triggered directly the rapid biogenesis of distinctive LTB4-synthesizing lipid bodies via CCR2-driven ERK- and PI3K-dependent intracellular signaling in in vitro-stimulated macrophages. Disturbance of microtubule organization by microtubule-active drugs demonstrated that MCP-1-induced lipid body biogenesis also signals through a pathway dependent on microtubular dynamics. Besides biogenic process, microtubules control LTB4-synthesizing function of MCP-1-elicited lipid bodies, in part by regulating the compartmentalization of key proteins, as adipose differentiation-related protein and 5-lipoxygenase. Therefore, infection-elicited MCP-1, besides its known CCR2-driven chemotactic function, appears as a key activator of lipid body biogenic and functional machineries, signaling through a microtubule-dependent manner.
Skin-Homing Receptors on Effector Leukocytes Are Differentially Sensitive to Glyco-Metabolic Antagonism in Allergic Contact Dermatitis
Authors: Gainers Madeliene E. , Descheny Leyla , Barthel Steven R. , Liu Luzheng , Wurbel Marc-André , Dimitroff Charles J. 
Published: April 2014

Abstract
T cell recruitment into inflamed skin is dependent on skin-homing receptor binding to endothelial (E)- and platelet (P)-selectin. These T cell receptors, or E- and P-selectin ligands, can be targeted by the metabolic fluorosugar inhibitor, 4-F-GlcNAc, to blunt cutaneous inflammation. Compelling new data indicate that, in addition to T cells, NK cells are also recruited to inflamed skin in allergic contact hypersensitivity (CHS) contingent on E- and P-selectin-binding. Using a model of allergic CHS, we evaluated the identity and impact of NK cell E-selectin ligand(s) on inflammatory responses and examined the oral efficacy of 4-F-GlcNAc. We demonstrated that the predominant E-selectin ligands on NK cells are P-selectin glycoprotein ligand-1 and protease-resistant glycolipids. We showed that, unlike the induced E-selectin ligand expression on activated T cells upon exposure to Ag, ligand expression on NK cells was constitutive. CHS responses were significantly lowered by orally administered 4-F-GlcNAc treatment. Although E-selectin ligand on activated T cells was suppressed, ligand expression on NK cells was insensitive to 4-F-GlcNAc treatment. These findings indicate that downregulating effector T cell E- and P-selectin ligand expression directly correlates with anti-inflammatory efficacy and provides new insight on metabolic discrepancies of E-selectin ligand biosynthesis in effector leukocytes in vivo.
NLRP2, an Inhibitor of the NF-κB Pathway, Is Transcriptionally Activated by NF-κB and Exhibits a Nonfunctional Allelic Variant
Authors: Fontalba Ana , Gutierrez Olga , Fernandez-Luna Jose L. 
Published: April 2014

Abstract
NLRP2 has been shown to inhibit the NF-κB signaling pathway, and thus may contribute to modulate the inflammatory response, where NF-κB plays a major role. In this study, we report that expression of NLRP2 is induced upon differentiation of CD34+ hemopoietic progenitors into granulocyte or monocyte/macrophages. We also found that NLRP2 was up-regulated following differentiation of mesenchymal stem cells toward adipocytes. Notably, stimulation of HEK293T cells with TNF-α or overexpression of the p65 subunit of NF-κB resulted in up-regulation of NLRP2 and the formation of NF-κB-NLRP2 promoter complexes. Moreover, ectopic expression of p65 but not of other transcriptional regulators induced transactivation of the NLRP2 promoter. Thus, NLRP2 may control NF-κB activation through a regulatory loop. Nucleotide changes within the NACHT domain of other NLRP proteins have been associated with hereditary fever syndromes and chronic inflammatory diseases. We identified five single nucleotide polymorphisms present in the NACHT domain of NLRP2 by sequencing genomic DNA from 319 healthy controls. The frequencies of the rare alleles varied between 0.2 and 10%. Of note, one of these variants, I352S was unable to block the transcriptional activity of NF-κB and the formation of NF-κB-DNA-binding complexes following stimulation with TNF-α. Overall, our findings provide molecular insight into the expression of NLRP2 by NF-κB and suggest that a polymorphism within the NACHT domain of NLRP2 may contribute to the amplification of inflammatory responses due to a reduction of inhibitory signals on the NF-κB pathway.
The Required Role of Endogenously Produced Lipoxin A4 and Annexin-1 for the Production of IL-10 and Inflammatory Hyporesponsiveness in Mice
Authors: Souza Danielle G. , Fagundes Caio T. , Amaral Flavio A. , Cisalpino Daniel , Sousa Lirlândia P. , Vieira Angélica T. , Pinho Vanessa , Nicoli Jacques R. , Vieira Leda Q. , Fierro Iolanda M. , Teixeira Mauro M. 
Published: April 2014

AbstractThe appropriate development of an inflammatory response is central for the ability of a host to deal with any infectious insult. However, excessive, misplaced, or uncontrolled inflammation may lead to acute or chronic diseases. The microbiota plays an important role in the control of inflammatory responsiveness. In this study, we investigated the role of lipoxin A4 and annexin-1 for the IL-10-dependent inflammatory hyporesponsiveness observed in germfree mice. Administration of a 15-epi-lipoxin A4 analog or an annexin-1-derived peptide to conventional mice prevented tissue injury, TNF-α production, and lethality after intestinal ischemia/reperfusion. This was associated with enhanced IL-10 production. Lipoxin A4 and annexin-1 failed to prevent reperfusion injury in IL-10-deficient mice. In germfree mice, there was enhanced expression of both lipoxin A4 and annexin-1. Blockade of lipoxin A4 synthesis with a 5-lipoxygenase inhibitor or Abs against annexin-1 partially prevented IL-10 production and this was accompanied by partial reversion of inflammatory hyporesponsiveness in germfree mice. Administration of BOC-1, an antagonist of ALX receptors (at which both lipoxin A4 and annexin-1 act), or simultaneous administration of 5-lipoxygenase inhibitor and anti-annexin-1 Abs, was associated with tissue injury, TNF-α production, and lethality similar to that found in conventional mice. Thus, our data demonstrate that inflammatory responsiveness is tightly controlled by the presence of the microbiota and that the innate capacity of germfree mice to produce IL-10 is secondary to their endogenous greater ability to produce lipoxin A4 and annexin-1.
IL-21 Induces Inhibitor of Differentiation 2 and Leads to Complete Abrogation of Anaphylaxis in Mice
Authors: Kishida Tsunao , Hiromura Yayoi , Shin-Ya Masaharu , Asada Hidetsugu , Kuriyama Hiroko , Sugai Manabu , Shimizu Akira , Yokota Yoshifumi , Hama Takemitsu , Imanishi Jiro , Hisa Yasuo , Mazda Osam 
Published: April 2014

Abstract
IL-21 exerts pleiotrophic immunomodulatory activities on a variety of target cells including B cells that undergo class switch recombination (CSR) to IgE. In this study, we examined whether IgE-mediated systemic anaphylaxis was controlled by in vivo administration of IL-21 using the peanut allergy model in mice and investigated the molecular mechanisms underlying the IL-21-induced regulation of IgE. The anaphylactic reaction was completely abolished by the administration of recombinant mouse IL-21 or an IL-21 expression plasmid in terms of the change of body temperature and anaphylactic symptoms. The recombinant mouse IL-21 treatment remarkably suppressed IgE CSR in splenic B cells, resulting in significant decrease in serum concentrations of total as well as allergen-specific IgE. In the meanwhile, IL-21 provoked B cells in normal as well as allergic mice to express the inhibitor of differentiation 2 (Id2) gene that was shown to be crucially involved in the regulation of the activation-induced cytidine deaminase and IgE CSR. Moreover, mice genetically deficient for Id2 were completely unsusceptible to IL-21-induced prevention of IgE CSR and anaphylaxis. The present study strongly suggests that IL-21 is capable of regulating systemic allergic reactions by inducing the transcriptional regulator Id2, and the cytokine may be useful for clinical intervention for allergic diseases including anaphylaxis.
Anti-C5 Antibody Treatment Ameliorates Weakness in Experimentally Acquired Myasthenia Gravis
Authors: Zhou Yuefang , Gong Bendi , Lin Feng , Rother Russell P. , Medof M. Edward , Kaminski Henry J. 
Published: April 2014

Abstract
Myasthenia gravis (MG) is a neuromuscular transmission disorder in which damage to acetylcholine receptors (AChR) on motor endplates by autoantibody-induced complement attack causes muscle weakness. To determine whether and, if so, to what extent, blockade of complement cascade at the C5 step ameliorates disease, we evaluated the effect of administering a functionally blocking anti-C5 mAb in passive experimental MG in Lewis rats induced with AChR Ab McAb-3. In contrast to uniform severe weakness at 24 h requiring euthanasia in untreated animals, anti-C5 mAb-pretreated rats showed no weakness at 48 h. Anti-C5 mAb treatment 24 h after disease induction restored strength in two-thirds of the rats. Immunofluorescence staining of endplates from the treated animals showed that C9 deposition at AChR was reduced and ultrastructural analyses showed that endplates were intact. The results argue that targeting C5 may warrant testing in MG patients and that this approach may be particularly valuable for myasthenic crisis.
Constitutive Expression of B7-1 on B Cells Uncovers Autoimmunity toward the B Cell Compartment in the Nonobese Diabetic Mouse
Authors: Bour-Jordan Hélène , Salomon Benoit L. , Thompson Heather L. , Santos Rex , Abbas Abul K. , Bluestone Jeffrey A. 
Published: April 2014

Abstract
The NOD mouse is an invaluable model for the study of autoimmune diabetes. Furthermore, although less appreciated, NOD mice are susceptible to other autoimmune diseases that can be differentially manifested by altering the balance of T cell costimulatory pathways. In this study, we show that constitutively expressing B7-1 on B cells (NOD-B7-1B-transgenic mice) resulted in reduced insulitis and completely protected NOD mice from developing diabetes. Furthermore, B7-1 expression led to a dramatic reduction of the B cell compartment due to a selective deletion of follicular B cells in the spleen, whereas marginal zone B cells were largely unaffected. B cell depletion was dependent on B cell specificity, mediated by CD8+ T cells, and occurred exclusively in the autoimmune-prone NOD background. Our results suggest that B cell deletion was a consequence of the specific activation of autoreactive T cells directed at peripheral self Ags presented by maturing B cells that expressed B7-1 costimulatory molecules. This study underscores the importance of B7 costimulatory molecules in controlling the amplitude and target of autoimmunity in genetically prone individuals and has important implications in the use of costimulatory pathway antagonists in the treatment of human autoimmune diseases.