bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macrophage Oxygen Sensing Modulates Antigen Presentation and Phagocytic Functions Involving IFN-γ Production through the HIF-1α Transcription Factor
Authors: Acosta-Iborra Bárbara , Elorza Ainara , Olazabal Isabel M. , Martín-Cofreces Noa B. , Martin-Puig Silvia , Miró Marta , Calzada María J. , Aragonés Julián , Sánchez-Madrid Francisco , Landázuri Manuel O. 
Published: February 2009

Abstract
Low oxygen tension areas are found in inflamed or diseased tissues where hypoxic cells induce survival pathways by regulating the hypoxia-inducible transcription factor (HIF). Macrophages are essential regulators of inflammation and, therefore, we have analyzed their response to hypoxia. Murine peritoneal elicited macrophages cultured under hypoxia produced higher levels of IFN-γ and IL-12 mRNA and protein than those cultured under normoxia. A similar IFN-γ increment was obtained with in vivo models using macrophages from mice exposed to atmospheric hypoxia. Our studies showed that IFN-γ induction was mediated through HIF-1α binding to its promoter on a new functional hypoxia response element. The requirement of HIF-α in the IFN-γ induction was confirmed in RAW264.7 cells, where HIF-1α was knocked down, as well as in resident HIF-1α null macrophages. Moreover, Ag presentation capacity was enhanced in hypoxia through the up-regulation of costimulatory and Ag-presenting receptor expression. Hypoxic macrophages generated productive immune synapses with CD8 T cells that were more efficient for activation of TCR/CD3ε, CD3ζ and linker for activation of T cell phosphorylation, and T cell cytokine production. In addition, hypoxic macrophages bound opsonized particles with a higher efficiency, increasing their phagocytic uptake, through the up-regulated expression of phagocytic receptors. These hypoxia-increased immune responses were markedly reduced in HIF-1α- and in IFN-γ-silenced macrophages, indicating a link between HIF-1α and IFN-γ in the functional responses of macrophages to hypoxia. Our data underscore an important role of hypoxia in the activation of macrophage cytokine production, Ag-presenting activity, and phagocytic activity due to an HIF-1α-mediated increase in IFN-γ levels.
Reduced Thymic Aire Expression and Abnormal NF-κB2 Signaling in a Model of Systemic Autoimmunity
Authors: Fletcher Anne L. , Seach Natalie , Reiseger Jessica J. , Lowen Tamara E. , Hammett Maree V. , Scott Hamish S. , Boyd Richard L. 
Published: February 2009

Abstract
The thymic stromal niche normally directs the production and export of a self-tolerant T cell repertoire. Many models of spontaneous autoimmunity, however, develop thymic architectural abnormalities before disease onset. Although this is suspected to affect central tolerance induction, creating an autoimmune predisposition, in-depth analysis of the microenvironment within these thymi is lacking, such that the mechanisms and likely direct effects on the T cell repertoire are unknown or speculative. Here we show that NZB mice, the first described model for systemic autoimmunity, demonstrate a complex thymic phenotype, including a lack of the autoimmune regulator (Aire), early defects in thymic epithelial cell (TEC) expansion, and evidence for altered NF-κB2 signaling. Analysis of medullary TEC revealed a numerical loss of the Aire-expressing MHC class IIhigh (mTEC-high) subset as well reduced Aire protein and mRNA per cell. RelB expression was also reduced, while chemokines CCL19 and CCL21 were increased. Unexpectedly, the proportion of cortex and medulla in the NZB mice was normal from 36 wk, despite worsening architectural abnormalities. These data show that the NZB defect is more complex than previously appreciated, segregating into early numerical TEC deficiencies that correct with age, late degeneration of the niche architecture that does not affect TEC number, and a persistent reduction in Aire and RelB expression per cell acquired upon mTEC-high differentiation.
Human SCAMP5, a Novel Secretory Carrier Membrane Protein, Facilitates Calcium-Triggered Cytokine Secretion by Interaction with SNARE Machinery
Authors: Han Chaofeng , Chen Taoyong , Yang Mingjin , Li Nan , Liu Haibo , Cao Xuetao 
Published: February 2009

Abstract
Cytokines produced by immune cells play pivotal roles in the regulation of both innate and adaptive immunity. However, the mechanisms controlling secretion of cytokines have not been fully elucidated. Secretory carrier membrane proteins (SCAMPs) are widely distributed integral membrane molecules implicated in regulating vesicular transport. In this study, we report the functional characterization of human SCAMP5 (hSCAMP5), a novel SCAMP protein that is widely expressed by a variety of neuronal and nonneuronal tissues and cells. By measuring the cytokine secretion (RANTES/CCL5 and IL-1β) as an exocytotic model, we show that hSCAMP5 can promote the calcium-regulated signal peptide-containing cytokine (CCL5 but not IL-1β) secretion in human epithelial cancer cells, human monocytes, and mouse macrophages. By using subcellular fractionation, immunofluorescence confocal microscopy, and membrane vesicle immunoisolation methods, we find that hSCAMP5 is mainly localized in the Golgi-associated compartments, and the calcium ionophore ionomycin can trigger a rapid translocation of hSCAMP5 from Golgi apparatus to plasma membrane along the classical exocytosis pathway. During the translocation of hSCAMP5 from Golgi apparatus to plasma membrane, hSCAMP5 can codistribute and complex with local soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs) molecules. We further demonstrate that hSCAMP5 can directly interact with the calcium sensor synaptotagmins via the cytosolic C-terminal tail of hSCAMP5, thus providing a potential molecular mechanism linking SCAMPs with the SNARE molecules. Our findings suggest that hSCAMP5, in cooperation with the SNARE machinery, is involved in calcium-regulated exocytosis of signal peptide-containing cytokines.
Peripheral T Cell Functions Correlate with the Severity of Chronic Obstructive Pulmonary Disease
Authors: Zhu Xuehai , Gadgil Aneal S. , Givelber Rachel , George M. Patricia , Stoner Michael W. , Sciurba Frank C. , Duncan Steven R. 
Published: February 2009

Abstract
Adaptive immune processes have been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). We hypothesized that peripheral T cell abnormalities may be present in afflicted patients. We tested this hypothesis by characterizing circulating T cells in COPD patients and correlated these findings with disease severity, smoking status, and use of inhaled glucocorticosteroids (ICS). Compared with normal controls, a lesser proportion of peripheral CD4 T cells from COPD subjects produced IL-10, whereas the CD8 T cells from these patients were more often activated and more frequently produced both IFN-γ and IL-4. COPD severity was significantly and inversely associated with the proportion of circulating CD4 T cells and directly correlated with CD4 production of IL-2, as well as frequency of CD8 T cell activation and CD8 IFN-γ production. Adjustments for current smoking status and ICS use by linear regression showed independent, and generally inhibitory, effects of these clinical variables on the abnormal T cell functions of these patients. We conclude that circulating T cells from COPD patients are abnormally activated and elaborate proinflammatory mediators with admixed features of Th1 and Th2 responses. Furthermore, many of these effector processes are significantly correlated with disease severity. These findings further implicate adaptive immune processes in COPD progression and indicate that facile assays of peripheral lymphocytes may provide useful insights into disease mechanisms. Current smoking and ICS use had independent effects on T cell functions among the COPD subjects, illustrating the importance of controlling for clinical parameters as covariates in immunological studies of patients afflicted with this disease.
Ultraviolet B Radiation Generated Platelet-Activating Factor Receptor Agonist Formation Involves EGF-R-Mediated Reactive Oxygen Species
Authors: Yao Yongxue , Wolverton Jay E. , Zhang Qiwei , Marathe Gopal K. , Al-Hassani Mohammed , Konger Raymond L. , Travers Jeffrey B. 
Published: February 2009

Abstract
Recent studies have implicated the lipid mediator platelet-activating factor (PAF) in UVB-mediated systemic immunosuppression known to be a major cause for skin cancers. Previously, our group has demonstrated that UVB irradiation triggers the production of PAF and oxidized glycerophosphocholines that act as PAF-receptor (PAF-R) agonists. The present studies explored the mechanisms by which UVB generates PAF-R agonists. UVB irradiation of human epidermal KB cells resulted in both increased levels of reactive oxygen species (ROS) and PAF-R agonistic activity. Pretreatment of KB cells with antioxidants vitamin C and N-acetylcysteine or the pharmacological inhibitor PD168393 specific for the epidermal growth factor receptor all inhibited UVB-induced ROS as well as PAF-R agonists, yet had no effect on fMLP-mediated PAF-R agonist production. In addition, in vivo production of PAF-R agonists from UVB-irradiated mouse skin was blocked by both systemic vitamin C administration and topical PD168393 application. Moreover, both vitamin C and PD168393 abolished UVB-mediated but not the PAF-R agonist 1-hexadecyl-2-N-methylcarbamoyl glycerophosphocholine-mediated immunosuppression as measured by the inhibition of delayed type contact hypersensitivity to the chemical dinitrofluorobenzene. These studies suggest that UVB-induced systemic immunosuppression is due to epidermal growth factor receptor-mediated ROS which results in PAF-R agonist formation.
IL-21 Mediates Suppressive Effects via Its Induction of IL-10
Authors: Spolski Rosanne , Kim Hyoung-Pyo , Zhu Wei , Levy David E. , Leonard Warren J. 
Published: February 2009

Abstract
IL-21 is a pleiotropic cytokine that is required for normal Ig production. We previously showed that IL-21 was elevated in BXSB-Yaa mice with systemic lupus erythematosus. These mice also had elevated IL-10 levels, and we now show that IL-21 induces IL-10 mRNA and protein, suggesting unexpected immunosuppressive activities for IL-21. Indeed, Th1 priming with IL-21 leads to accumulation of cells with immunosuppressive activity, and IL-21 overexpression decreases specific Ab production after immunization in an IL-10-dependent fashion. Moreover, we show that IL-21 signaling is required for maximal induction of IL-10 by IL-6 or IL-27. Overall, our data indicate that IL-21 regulates immune responses at least in part by inducing IL-10 and reveal unanticipated immunosuppressive actions for this cytokine.
High Resolution Mapping of Cia3: A Common Arthritis Quantitative Trait Loci in Different Species
Authors: Yu Xinhua , Teng Haidong , Marques Andreia , Ashgari Farahnaz , Ibrahim Saleh M. 
Published: February 2009

Abstract
Murine collagen induced arthritis (CIA) is a widely used model of rheumatoid arthritis (RA). Identification of CIA susceptibility genes will aid in the understanding of RA pathogenesis and development of therapeutic targets. This study aims to identify and refine quantitative trait loci (QTL) controlling CIA. Major CIA clinical traits were evaluated in both (DBA/1×FVB/N) F2 and advanced intercross line (AIL) mice; QTLs were confirmed and refined in AIL. To search for candidate genes, we applied multiple approaches, including gene expression profiling, identification of nonsynonymous polymorphism, and comparative genomic mapping. We identified six suggestive QTLs controlling CIA clinical traits in the F2 progeny; one of these was confirmed and refined in AIL. This QTL is located on chromosome 6 and overlaps with Cia3, which was identified previously. We refined the 2-log support interval of Cia3 into a 5.6 Mb genomic region; 15 of 77 genes are differentially expressed or carry nonsynonymous polymorphisms between two parental strains. The counterpart genomic region of Cia3 on the rat and human genomes are linked to RA. Twenty-nine of 77 genes are located in the arthritis-linked genomic regions of all three species. Five of those 29 genes are differentially expressed or carry nonsynonymous polymorphisms between parental strains: Timp4, Tmem40, Mbd4, Cacna1c, and Lrtm2. Taken together, we refined Cia3 into a 5.6 Mb genomic region on mouse chromosome 6 and identified candidate genes. This will aid in the search for susceptibility gene(s) controlling arthritis development within Cia3 and its counterpart regions in rat and human genomes.
FcRn in the Yolk Sac Endoderm of Mouse Is Required for IgG Transport to Fetus
Authors: Kim Jonghan , Mohanty Sudhasri , Ganesan Latha P. , Hua Keding , Jarjoura David , Hayton William L. , Robinson John M. , Anderson Clark L. 
Published: February 2009

Abstract
In adults, the nonclassical MHC class I molecule, FcRn, binds both IgG and albumin and rescues both from a degradative fate, endowing both proteins with high plasma concentrations. FcRn also transports IgG from mother to young during gestation. Anticipating that a detailed understanding of gestational IgG transport in the mouse may give us a useful model to understand FcRn function in the human placenta, we have studied FcRn in the mouse yolk sac placenta in detail. Analyzing day 19–20 fetuses of the three FcRn genotypes resulting from matings of FcRn+/− parents, we found that FcRn−/− fetuses showed negligible IgG concentrations (1.5 μg/ml), whereas IgG concentrations in FcRn+/− fetuses were about a half (176 μg/ml) that of FcRn+/+ fetuses (336 μg/ml), indicating that FcRn is responsible for virtually all IgG transport from mother to fetus. Immunofluorescence and immunoblotting studies indicated that FcRn is expressed in the endoderm of the yolk sac placenta but not in other cells of the yolk sac placenta or in the chorioallantoic placenta. IgG was found in the endoderm of both FcRn+/+ and FcRn−/− yolk sac placentas and in the mesenchyme of FcRn+/+ but was missing from the mesenchyme of FcRn−/− yolk sac placentas, indicating that IgG enters the endoderm constitutively but is moved out of the endoderm by FcRn. The similarities of these results to human placental FcRn expression and function are striking.
Antigen Processing and MHC-II Presentation by Dermal and Tumor-Infiltrating Dendritic Cells
Authors: Gerner Michael Y. , Mescher Matthew F. 
Published: February 2009

Abstract
MHC-II presentation by dendritic cells (DC) is necessary both for initial priming of CD4 T cells and for induction of peripheral effector function. Although CD4 T cells can be critical for competent immunization-mediated cancer immunosurveillance, unmanipulated CD4 T cell responses to poorly immunogenic tumors result in either complete ignorance or tolerance induction, suggesting inadequate DC function. In this study, we investigated the phenotype, Ag uptake, and MHC-II presentation capacity of normal dermal DC and tumor-infiltrating DC (TIDC) in both lymphoid and peripheral sites. We found that murine tumors were extensively infiltrated by partially activated TIDC that closely resembled dermal DC by surface marker expression. However, in contrast to dermal DC, TIDC were inefficient at MHC-II presentation due to poor intrinsic protein uptake capability. This resulted in both inferior initiation of T cell responses in the draining lymph node and poor peripheral effector cell accumulation. In addition, TLR stimulation selectively enhanced MHC-II presentation of Ag by dermal DC, but not TIDC in the draining lymph node, and did not affect overall peripheral Ag uptake of either. These results show that TIDC are functionally distinct from normal interstitial DC, thus indicating that neoplastic tissues can evade effector CD4 T cells through modification of DC competence.
Selective Inhibition of CCR2 Expressing Lymphomyeloid Cells in Experimental Autoimmune Encephalomyelitis by a GM-CSF-MCP1 Fusokine
Authors: Rafei Moutih , Campeau Philippe M. , Wu Jian Hui , Birman Elena , Forner Kathy , Boivin Marie-Noelle , Galipeau Jacques 
Published: February 2009

Abstract
We describe the generation of a fusion cytokine consisting of GM-CSF in tandem with N-terminal-truncated MCP-1 (6-76), hereafter GMME1. Treatment of activated T cells with recombinant GMME1 protein leads to proinflammatory cytokine reduction and apoptosis via a CCR2-restricted pathway. Similarly, cell death is triggered in macrophages cultured with GMME1, while an inhibition of Ab production from plasma cells is observed. Treatment of CD4 T cells derived from experimental autoimmune encephalomyelitis mice with GMME1 leads to p38 hyperphosphorylation, inhibition of p44/42, AKT and STAT3 phosphorylation, and caspase-3 activation. GMME1 administration to experimental autoimmune encephalomyelitis mice suppresses symptomatic disease and correlates with decreased levels of inflammatory cytokines including IL-17, MOG-specific Ab titers, and blockade of CD4 and CD8 T cell infiltration in spinal cords. We propose that GMME1 defines a new class of agents for the treatment of autoimmune ailments by selectively targeting lymphomyeloid cells expressing CCR2.
Bone Marrow Chimeras and c-fms Conditional Ablation (Mafia) Mice Reveal an Essential Role for Resident Myeloid Cells in Lipopolysaccharide/TLR4-Induced Corneal Inflammation
Authors: Chinnery Holly R. , Carlson Eric C. , Sun Yan , Lin Michelle , Burnett Sandra H. , Perez Victor L. , McMenamin Paul G. , Pearlman Eric 
Published: February 2009

Abstract
The mammalian cornea contains an extensive network of resident macrophages and dendritic cells. To determine the role of these cells in LPS-induced corneal inflammation, TLR4−/− mice were sublethally irradiated and reconstituted with bone marrow cells from either enhanced GFP (eGFP)+/C57BL/6 or eGFP+/TLR4−/− mice. The corneal epithelium was abraded, LPS was added topically, and cellular infiltration to the corneal stroma and development of corneal haze were examined after 24 h. TLR4−/− mice reconstituted with C57BL/6, but not TLR4−/− bone marrow cells donor cells were found to cause infiltration of eGFP+ cells to the cornea, including neutrophils, and also increased corneal haze compared with saline-treated corneas. In a second experimental approach, corneas of transgenic macrophage Fas induced apoptosis (Mafia) mice were stimulated with LPS. These mice express eGFP and a suicide gene under control of the c-fms promoter, and systemic treatment with the FK506 dimerizer (AP20187) causes Fas-mediated apoptosis of monocytic cells. AP20187-treated mice had significantly fewer eGFP+ cells in the cornea than untreated mice. After stimulation with LPS neutrophil recruitment and development of corneal haze were impaired in AP20187-treated mice compared with untreated controls. Furthermore, LPS induced CXCL1/KC and IL-1α production within 4 h in corneas of untreated Mafia mice, which is before cellular infiltration; however, cytokine production was impaired after AP20187 treatment. Together, results from both experimental approaches demonstrate an essential role for resident corneal monocytic lineage cells (macrophages and dendritic cells) in development of corneal inflammation.
Preferential Use of B7.2 and Not B7.1 in Priming of Vaccinia Virus-Specific CD8 T Cells
Authors: Salek-Ardakani Shahram , Arens Ramon , Flynn Rachel , Sette Alessandro , Schoenberger Stephen P. , Croft Michael 
Published: February 2009

Abstract
Recent studies have demonstrated that CD28 provides critical costimulatory signals required for optimal CD8 T cell expansion and effector function in response to several viruses, including influenza, HSV, and vaccinia virus (VACV). CD28 has two ligands expressed largely on professional APC, named B7.1 (CD80) and B7.2 (CD86). Although some results suggest that these ligands are equivalent and both promote CD28 signaling, it is not clear whether they are equally important for priming of antiviral T cells. Herein we show that B7.2 is critical for early CD8 T cell responses to both dominant and subdominant VACV epitopes, correlating with its strong induction on CD8α+ dendritic cells. In contrast, B7.1 plays no significant role. Signals from an exogenously applied adjuvant can recruit B7.1 activity and lead to further enhanced priming of VACV-reactive CD8 T cells. However, during a natural infection, B7.1 is not functional, likely related to inefficient up-regulation or active suppression by VACV. These studies provide evidence that B7.2 is the major ligand for the CD28 receptor on VACV-specific CD8 T cells, that B7.2 can promote efficient CD8 T cell priming without B7.1, and that B7.1 and B7.2 can be differentially utilized during antiviral responses.
Mapping of a Microbial Protein Domain Involved in Binding and Activation of the TLR2/TLR1 Heterodimer
Authors: Liang Shuang , Hosur Kavita B. , Lu Shanyun , Nawar Hesham F. , Weber Benjamin R. , Tapping Richard I. , Connell Terry D. , Hajishengallis George 
Published: February 2009

Abstract
The pentameric B subunit of type IIb Escherichia coli enterotoxin (LT-IIb-B5), a doughnut-shaped oligomeric protein from enterotoxigenic E. coli, activates the TLR2/TLR1 heterodimer (TLR2/1). We investigated the molecular basis of the LT-IIb-B5 interaction with TLR2/1 to define the structure-function relationship of LT-IIb-B5 and, moreover, to gain an insight into how TLR2/1 recognizes large, nonacylated protein ligands that cannot fit within its lipid-binding pockets, as previously shown for the Pam3CysSerLys4 (Pam3CSK4) lipopeptide. We first identified four critical residues in the upper region of the LT-IIb-B5 pore. Corresponding point mutants (M69E, A70D, L73E, S74D) were defective in binding TLR2 or TLR1 and could not activate APCs, despite retaining full ganglioside-binding capacity. Point mutations in the TLR2/1 dimer interface, as determined in the crystallographic structure of the TLR2/1-Pam3CSK4 complex, resulted in diminished activation by both Pam3CSK4 and LT-IIb-B5. Docking analysis of the LT-IIb-B5 interaction with this apparently predominant activation conformation of TLR2/1 revealed that LT-IIb-B5 might primarily contact the convex surface of the TLR2 central domain. Although the TLR1/LT-IIb-B5 interface is relatively smaller, the leucine-rich repeat motifs 9–12 in the central domain of TLR1 were found to be critical for cooperative TLR2-induced cell activation by LT-IIb-B5. Moreover, the putative LT-IIb-B5 binding site overlaps partially with that of Pam3CSK4; consistent with this, Pam3CSK4 suppressed TLR2 binding of LT-IIb-B5, albeit not as potently as self-competitive inhibition. We identified the upper pore region of LT-IIb-B5 as a TLR2/1 interactive domain, which contacts the heterodimeric receptor at a site that is distinct from, although it overlaps with, that of Pam3CSK4.