bluuebunny/crossref_metadata_2025_split huggingface dataset:
B7-DC Regulates Asthmatic Response by an IFN-γ-Dependent Mechanism
Authors: Matsumoto Koichiro , Inoue Hiromasa , Nakano Takako , Tsuda Miyuki , Yoshiura Yuki , Fukuyama Satoru , Tsushima Fumihiko , Hoshino Tomoaki , Aizawa Hisamichi , Akiba Hisaya , Pardoll Drew , Hara Nobuyuki , Yagita Hideo , Azuma Miyuki , Nakanishi Yoichi 
Published: April 2014

Abstract
B7-H1 (PD-L1) and B7-DC (PD-L2) are the ligands for programmed death-1 (PD-1), which is a member of the CD28/CTLA-4 family and has been implicated in peripheral tolerance. We investigated the roles of B7-H1 and B7-DC in a murine OVA-induced allergic asthma model. B7-H1 was constitutively expressed on dendritic cells, macrophages, B cells, and T cells in the lungs of naive mice, and its expression could be dramatically increased after allergen challenge. In contrast, B7-DC expression was scarcely expressed on dendritic cells in naive mice, but was up-regulated after allergen challenge, although the up-regulation of B7-DC expression on macrophages was minimal. Treatment of mice with anti-B7-DC mAb at the time of allergen challenge, but not at the time of sensitization, significantly increased their airway hyper-reactivity and eosinophilia. Such treatment also resulted in the increased production of IL-5 and IL-13, and decreased IFN-γ production in the lungs and draining lymph node cells. These changes were diminished when mice were depleted of IFN-γ by anti-IFN-γ mAb pretreatment. Interestingly, treatment with anti-B7-H1 or anti-PD-1 mAb did not significantly affect the asthmatic response. These results suggest a unique role for B7-DC in the regulation of asthmatic response through an IFN-γ-dependent, but PD-1-independent, mechanism.
Microtubule-Associated Serine/Threonine Kinase-205 kDa and Fcγ Receptor Control IL-12 p40 Synthesis and NF-κB Activation
Authors: Zhou Hui , Xiong Huabao , Li Hongxing , Plevy Scott E. , Walden Paul D. , Sassaroli Massimo , Prestwich Glenn D. , Unkeless Jay C. 
Published: April 2014

Abstract
Stimulation of murine macrophages with LPS results in the coordinated activation of a set of proinflammatory cytokines and costimulatory molecules, including TNF-α, IL-6, IL-1, IL-8, IL-12, and CD80. Macrophage LPS-induced synthesis of IL-12 is inhibited following FcγR ligation; TNF-α secretion is unchanged. We report that microtubule-associated serine/threonine kinase-205 kDa (MAST205) is required for LPS-induced IL-12 synthesis. RNA interference-mediated suppression of MAST205 results in the inhibition of LPS-stimulated IL-12 promoter activity and IL-12 secretion, from both J774 cells and bone marrow-derived macrophages. Similarly, dominant-negative MAST205 mutants inhibit LPS-stimulated IL-12 synthesis and NF-κB activation, but do not affect IL-1 or TNF-α signaling. Finally, macrophage FcγR ligation regulates MAST205 by inducing the rapid ubiquitination and proteasomal degradation of the protein.
Inhibition of c-Jun NH2-Terminal Kinase Activity Improves Ischemia/Reperfusion Injury in Rat Lungs
Authors: Ishii Makoto , Suzuki Yukio , Takeshita Kei , Miyao Naoki , Kudo Hiroyasu , Hiraoka Rika , Nishio Kazumi , Sato Nagato , Naoki Katsuhiko , Aoki Takuya , Yamaguchi Kazuhiro 
Published: April 2014

Abstract
Although c-Jun NH2-terminal kinase (JNK) has been implicated in the pathogenesis of transplantation-induced ischemia/reperfusion (I/R) injury in various organs, its significance in lung transplantation has not been conclusively elucidated. We therefore attempted to measure the transitional changes in JNK and AP-1 activities in I/R-injured lungs. Subsequently, we assessed the effects of JNK inhibition by the three agents including SP600125 on the degree of lung injury assessed by means of various biological markers in bronchoalveolar lavage fluid and histological examination including detection of apoptosis. In addition, we evaluated the changes in p38, extracellular signal-regulated kinase, and NF-κB-DNA binding activity. I/R injury was established in the isolated rat lung preserved in modified Euro-Collins solution at 4°C for 4 h followed by reperfusion at 37°C for 3 h. We found that AP-1 was transiently activated during ischemia but showed sustained activation during reperfusion, leading to significant lung injury and apoptosis. The change in AP-1 was generally in parallel with that of JNK, which was activated in epithelial cells (bronchial and alveolar), alveolar macrophages, and smooth muscle cells (bronchial and vascular) on immunohistochemical examination. The change in NF-κB qualitatively differed from that of AP-1. Protein leakage, release of lactate dehydrogenase and TNF-α into bronchoalveolar lavage fluid, and lung injury were improved, and apoptosis was suppressed by JNK inhibition. In conclusion, JNK plays a pivotal role in mediating lung injury caused by I/R. Therefore, inhibition of JNK activity has potential as an effective therapeutic strategy for preventing I/R injury during lung transplantation.
Peptide-Mediated Inhibition of Neutrophil Transmigration by Blocking CD47 Interactions with Signal Regulatory Protein α
Authors: Liu Yuan , O’Connor Miriam B. , Mandell Kenneth J. , Zen Ke , Ullrich Axel , Bühring Hans-Jörg , Parkos Charles A. 
Published: April 2014

Abstract
CD47, a cell surface transmembrane Ig superfamily member, is an extracellular ligand for signal regulatory protein (SIRPα). Interactions between CD47 and SIRPα regulate many important immune cell functions including neutrophil (PMN) transmigration. Here we report identification of a novel function-blocking peptide, CERVIGTGWVRC, that structurally mimics an epitope on CD47 and binds to SIRPα. The CERVIGTGWVRC sequence was identified by panning phage display libraries on the inhibitory CD47 mAb, C5D5. In vitro PMN migration assays demonstrated that peptide CERVIGTGWVRC specifically inhibited PMN migration across intestinal epithelial monolayers and matrix in a dose-dependent fashion. Further studies using recombinant proteins indicated that the peptide specifically blocks CD47 and SIRPα binding in a dose-dependent fashion. Protein binding assays using SIRPα domain-specific recombinant proteins demonstrated that this peptide directly bound to the distal-most Ig loop of SIRPα, the same loop where CD47 binds. In summary, these findings support the relevance of CD47-SIRPα interactions in regulation of PMN transmigration and provide structural data predicting the key residues involved on the surface of CD47. Such peptide reagents may be useful for studies on experimental models of inflammation and provide a template for the design of anti-inflammatory agents.
Matrix Metalloproteinase-9 Deficiency Results in Enhanced Allergen-Induced Airway Inflammation
Authors: McMillan Sarah J. , Kearley Jennifer , Campbell J. Darren , Zhu Xing-Wu , Larbi Karen Y. , Shipley J. Michael , Senior Robert M. , Nourshargh Sussan , Lloyd Clare M. 
Published: April 2014

Abstract
Matrix metalloproteinases (MMPs) are a large family of endopeptidases that proteolytically degrade extracellular matrix. Many different cells produce MMP-9, and levels have been shown to be up-regulated in patients with allergic asthma. The aim of this study was to investigate the in vivo role of MMP-9 during allergen-induced airway inflammation. Acute allergic pulmonary eosinophilia was established in MMP-9 knockout (KO) and wild-type (WT) control mice by sensitization and challenge with OVA. Cell recruitment was significantly increased in both bronchoalveolar lavage (BAL) and lung tissue compartments in MMP-9 KO mice compared with WT mice. This heightened cell recruitment was primarily due to increased eosinophils and Th2 cells in the BAL and lung tissue of MMP-9 KO mice in comparison with WT controls. Moreover, levels of the Th2 cytokines, IL-4 and IL-13, and the chemokines eotaxin/CCL11 and macrophage-derived chemokine/CCL22 were substantially increased in MMP-9 KO mice compared with WT after OVA challenge. Resolution of eosinophilia was similar between MMP-9 KO and WT mice, but Th2 cells persisted in BAL and lungs of MMP-9 KO mice for longer than in WT mice. Our results indicate that MMP-9 is critically involved in the recruitment of eosinophils and Th2 cells to the lung following allergen challenge, and suggest that MMP-9 plays a role in the development of Th2 responses to allergen.
Role of Toll-Like Receptor 4 in Endotoxin-Induced Acute Renal Failure
Authors: Cunningham Patrick N. , Wang Ying , Guo Rongqing , He Gang , Quigg Richard J. 
Published: April 2014

Abstract
Toll-like receptor 4 (TLR4) is present on monocytes and other cell types, and mediates inflammatory events such as the release of TNF after exposure to LPS. C3H/HeJ mice are resistant to LPS-induced mortality, due to a naturally occurring mutation in TLR4. We therefore hypothesized that LPS-induced acute renal failure (ARF) requires systemic TNF release triggered by LPS acting on extrarenal TLR4. We injected C3H/HeJ mice and C3H/HeOuJ controls with 0.25 mg of LPS, and sacrificed them 6 h later for analysis of blood urea nitrogen (BUN) and kidney tissue (n = 8 per group). In contrast to C3H/HeOuJ controls, C3H/HeJ mice were completely resistant to LPS-induced ARF (6-h BUN of 32.3 ± 1.1 vs 61.7 ± 5.6 mg/dl). C3H/HeJ mice released no TNF into the circulation at 2 h (0.00 vs 1.24 ± 0.16 ng/ml), had less renal neutrophil infiltration (6.4 ± 1.0 vs 11.4 ± 1.3 neutrophils per high power field), and less renal apoptosis, as assessed by DNA laddering. Transplant studies showed that C3H/HeJ recipients of wild-type kidneys (n = 9) were protected from LPS-induced ARF, while wild-type recipients of C3H/HeJ kidneys (n = 11) developed severe LPS-induced ARF (24-h BUN 44.0 ± 4.1 vs 112.1 ± 20.0 mg/dl). These experiments support our hypothesis that LPS acts on extrarenal TLR4, thereby leading to systemic TNF release and subsequent ARF. Renal neutrophil infiltration and renal cell apoptosis are potential mechanisms by which endotoxemia leads to functional ARF.
TNF-α Coupled to Membrane of Apoptotic Cells Favors the Cross-Priming to Melanoma Antigens
Authors: Zimmermann Valérie S. , Bondanza Attilio , Monno Antonella , Rovere-Querini Patrizia , Corti Angelo , Manfredi Angelo A. 
Published: April 2014

Abstract
The cross-presentation of Ags derived from apoptotic cell processing contributes to peripheral tolerance. Environmental signals possibly modify this default outcome, favoring cross-priming. In this study, we anchored via a biotin-avidin-biotin bridge soluble TNF-α to the membrane of apoptotic melanoma cells and studied in vivo and in vitro the interaction with Ag-presenting phagocytes. TNF-α-coated apoptotic melanoma cells injected s.c. had a faster and more efficient access to draining lymph nodes, with cross-priming of melanoma-specific CTLs and delayed outgrowth of melanomas in all treated animals. Twenty percent of the animals, in the absence of further adjuvant, did not develop the tumor. Immature dendritic cells challenged with TNF-α-coated apoptotic melanoma cells secreted proinflammatory cytokines in an autocrine/paracrine fashion, efficiently matured, as assessed functionally and by flow cytometry and cross-presented with enhanced efficiency melanoma Ags to MHC class I- and II-restricted T cells. The results indicate that TNF-α targeted to apoptotic membranes, at concentrations that can be safely reached in growing tumors without undue systemic toxicity, influences the outcome of the disposal of dying cells and enhances tumor immunogenicity.
In Vivo Evidence That Peptide Vaccination Can Induce HLA-DR-Restricted CD4+ T Cells Reactive to a Class I Tumor Peptide
Authors: Harada Mamoru , Gohara Rumi , Matsueda Satoko , Muto Akira , Oda Tatsuya , Iwamoto Yoshiko , Itoh Kyogo 
Published: April 2014

Abstract
Vaccination with class I tumor peptides has been performed to induce tumor-reactive CD8+ T cells in vivo. However, the kinds of immune responses that vaccination might elicit in patients are not fully understood. In this study we tried to elucidate the mechanisms by which vaccination of class I binding tumor peptides into an HLA-A2+ lung cancer patient elicited dramatic amounts of IgG1 and IgG2 specific to a nonamer peptide, ubiquitin-conjugated enzyme variant Kua (UBE2V)43–51. The UBE2V43–51 peptide contains cysteine at the sixth position. HLA-DR-restricted and UBE2V43–51 peptide-recognizing CD4+ T cells were induced from postvaccination, but not from prevaccination, PBMCs of the cancer patient. In addition, a CD4+ T cell line (UB-2) and its clone (UB-2.3), both of which recognize the UBE2V43–51 peptide in the context of HLA-DRB1*0403 molecules, were successfully established from postvaccination PBMCs. The peptide vaccination increased the frequency of peptide-specific T cells, especially CD4+ T cells. In contrast, mass spectrometric analysis revealed that the vaccinated UBE2V43–51 peptide contained both monomeric and dimeric forms. Both forms, fractionated by reverse phase HPLC, were recognized by UB-2 and UB-2.3 cells. Recognition by these CD4+ T cells was observed despite the addition of a reduction reagent or the fixation of APC. Overall, these results indicate that vaccination with class I tumor peptides can induce HLA-DR-restricted CD4+ T cells in vivo and elicit humoral immune responses, and that a cysteine-containing peptide can be recognized by CD4+ T cells not only as a monomer, but also as a dimer.
Cutting Edge: Membrane Nanotubes Connect Immune Cells
Authors: Önfelt Björn , Nedvetzki Shlomo , Yanagi Kumiko , Davis Daniel M. 
Published: April 2014

Abstract
We present evidence that nanotubular highways, or membrane nanotubes, facilitate a novel mechanism for intercellular communication in the immune system. Nanotubes were seen to connect multiple cells together and were readily formed between a variety of cell types, including human peripheral blood NK cells, macrophages, and EBV-transformed B cells. Nanotubes could be created upon disassembly of the immunological synapse, as cells move apart. Thus, nanotubular networks could be assembled from transient immunological synapses. Nanotubes were seen to contain GFP-tagged cell surface class I MHC protein expressed in one of the connected cells. Moreover, GPI-conjugated to GFP originating from one cell was transferred onto the surface of another at the connection with a nanotube. Thus, nanotubes can traffic cell surface proteins between immune cells over many tens of microns. Determining whether there are physiological functions for nanotubes is an intriguing new goal for cellular immunology.
Cutting Edge: Innate Production of IFN-γ by NK Cells Is Independent of Epigenetic Modification of the IFN-γ Promoter
Authors: Tato Cristina M. , Martins Gislâine A. , High Frances A. , DiCioccio Catherine B. , Reiner Steven L. , Hunter Christopher A. 
Published: April 2014

Abstract
The ability of NK and T cells to produce IFN-γ is critical for resistance to numerous intracellular pathogens but the kinetics of these responses differ. Consistent with this is a requirement for naive T cells to become activated and undergo proliferation-dependent epigenetic changes to the IFN-γ locus that allow them to produce IFN-γ. The data presented here reveal that unlike T cells, murine NK cells produce IFN-γ under conditions of short-term cytokine stimulation, and these events are independent of proliferation and cell cycle progression. Furthermore, analysis of the IFN-γ locus in NK cells reveals that this locus is constitutively demethylated. The finding that NK cells do not need to remodel the IFN-γ locus to produce IFN-γ, either because they do not exhibit epigenetic repression or they have undergone prior remodeling during development, provides a molecular basis for the innate and adaptive regulation of the production of this cytokine.
Termination of Antigen-Specific Immunity by CD95 Ligand (Fas Ligand) and IL-10
Authors: Barreiro Ramon , Luker Gary , Herndon John , Ferguson Thomas A. 
Published: April 2014

Abstract
Following elimination of a foreign invader, the immune system must return to its normal quiescent levels. This process requires removal of reactive immune cells when they are no longer needed. We have explored the role of Fas/Fas ligand (FasL) in terminating immunity and demonstrate that mice defective in these proteins have prolonged immune responses. Studies demonstrate that termination of immunity occurs via the interaction of Fas+ lymphoid cells with FasL+ nonlymphoid cells at the site of Ag challenge. Our results also show that FasL is absent in quiescent tissue but is rapidly up-regulated during the local immune reaction. This occurs through the production of IL-10. Thus, FasL and IL-10 work in concert to eliminate inflammatory cells and control the duration of an immune response.
Antigen-Processing Machinery in Human Dendritic Cells: Up-Regulation by Maturation and Down-Regulation by Tumor Cells
Authors: Whiteside Theresa L. , Stanson Joanna , Shurin Michael R. , Ferrone Soldano 
Published: April 2014

Abstract
It has been known for some time that functional properties of dendritic cells (DC), and in particular their ability to process and present Ags to T cells, can be modulated by cytokine-induced maturation and by interactions with tumor cells. However, the molecular basis for these functional changes is unknown. We have investigated whether changes in expression of Ag-processing machinery (APM) components in DC are associated with alterations in their ability to present tumor-derived Ags to T cells. Using a panel of mAbs specific for individual APM components and a quantitative flow cytometry-based method, the level of APM components was measured in DC generated from peripheral blood monocytes of 12 normal donors and of 8 patients with cancer. Immature DC had significantly lower (p &lt; 0.01) expression of MB1, LMP-7, LMP-10, TAP-1, and tapasin than mature DC. However, maturation in the presence of a cytokine mixture up-regulated expression of these components in DC obtained from normal donors and patients with cancer. Immature DC incubated with tumor cells had significantly lower (p &lt; 0.001) expression of MB1, LMP-2, LMP-7, LMP-10, and endoplasmic reticulum p75 than controls. These changes were associated with a decreased ability of DC to present tumor-derived Ags to T cells, as measured in ELISPOT assays and with apoptosis of T cells in DC-T cell cultures. Thus, tumor cells have a significant suppressive effect on DC; however, ex vivo maturation of DC derived from patients with cancer in a polarizing cytokine mix restores normal expression of APM components and Ag-processing capabilities.
In Vivo Pattern of Lipopolysaccharide and Anti-CD3-Induced NF-κB Activation Using a Novel Gene-Targeted Enhanced GFP Reporter Gene Mouse
Authors: Magness Scott T. , Jijon Humberto , Van Houten Fisher Nancy , Sharpless Ned E. , Brenner David A. , Jobin Christian 
Published: April 2014

Abstract
NF-κB is a family of transcription factors involved in regulating cell death/survival, differentiation, and inflammation. Although the transactivation ability of NF-κB has been extensively studied in vitro, limited information is available on the spatial and temporal transactivation pattern in vivo. To investigate the kinetics and cellular localization of NF-κB-induced transcription, we created a transgenic mouse expressing the enhanced GFP (EGFP) under the transcriptional control of NF-κB cis elements (cis-NF-κBEGFP). A gene-targeting approach was used to insert a single copy of a NF-κB-dependent EGFP reporter gene 5′ of the X-linked hypoxanthine phosphoribosyltransferase locus in mouse embryonic stem cells. Embryonic fibroblasts, hepatic stellate cells, splenocytes, and dendritic cells isolated from cis-NF-κBEGFP mice demonstrated a strong induction of EGFP in response to LPS, anti-CD3, or TNF-α that was blocked by the NF-κB inhibitors BAY 11-0782 and NEMO-binding peptide. Chromatin immunoprecipitation analysis demonstrated RelA binding to the cis-NF-κBEGFP promoter. Adenoviral delivery of NF-κB-inducing kinase strongly induced EGFP expression in the liver of cis-NF-κBEGFP mice. Similarly, mice injected with anti-CD3 or LPS showed increased EGFP expression in mononuclear cells, lymph node, spleen, and liver as measured by flow cytometry and/or fluorescence microscopy. Using whole organ imaging, LPS selectively induced EGFP expression in the duodenum and proximal jejunum, but not in the ileum and colon. Confocal analysis indicated EGFP expression was primarily found in lamina propria mononuclear cells. In summary, the cis-NF-κBEGFP mouse will serve as a valuable tool to address multiple questions regarding the cell-specific and real-time activation of NF-κB during normal and diseased states.
Differences in the Kinetics, Amplitude, and Localization of ERK Activation in Anergy and Priming Revealed at the Level of Individual Primary T Cells by Laser Scanning Cytometry
Authors: Adams Claire L. , Grierson Angela M. , Mowat Allan M. , Harnett Margaret M. , Garside Paul 
Published: April 2014

AbstractOne of the potential mechanisms of peripheral tolerance is the unresponsiveness of T cells to secondary antigenic stimulation as a result of the induction of anergy. It has been widely reported that antigenic unresponsiveness may be due to uncoupling of MAPK signal transduction pathways. However, such signaling defects in anergic T cell populations have been mainly identified using immortalized T cell lines or T cell clones, which do not truly represent primary Ag-specific T cells. We have therefore attempted to quantify signaling events in murine primary Ag-specific T cells on an individual cell basis, using laser-scanning cytometry. We show that there are marked differences in the amplitude and cellular localization of phosphorylated ERK p42/p44 (ERK1/2) signals when naive, primed and anergic T cells are challenged with peptide-pulsed dendritic cells. Primed T cells display more rapid kinetics of phosphorylation and activation of ERK than naive T cells, whereas anergic T cells display a reduced ability to activate ERK1/2 upon challenge. In addition, the low levels of pERK found in anergic T cells are distributed diffusely throughout the cell, whereas in primed T cells, pERK appears to be targeted to the same regions of the cell as the TCR. These data suggest that the different consequences of Ag recognition by T cells are associated with distinctive kinetics, amplitude, and localization of MAPK signaling.
γδ T Cell Regulation of IFN-γ Production by Central Nervous System-Infiltrating Encephalitogenic T Cells: Correlation with Recovery from Experimental Autoimmune Encephalomyelitis
Authors: Ponomarev Eugene D. , Novikova Marina , Yassai Maryam , Szczepanik Marian , Gorski Jack , Dittel Bonnie N. 
Published: April 2014

AbstractInterferon-γ has been shown to be important for the resolution of inflammation associated with CNS autoimmunity. Because one of the roles of γδ T cells is the regulation of inflammation, we asked whether γδ T cells were able to regulate CNS inflammation using the autoimmune disease mouse model experimental autoimmune encephalomyelitis (EAE). We show that the presence of γδ T cells was needed to promote the production of IFN-γ by both CD4 and CD8 T cells in the CNS before the onset of EAE. This regulation was shown to be independent of the ability of γδ T cells to produce IFN-γ, and was specific to T cells in the CNS, as no alterations in IFN-γ production were detectable in γδ T cell-deficient mice in the spleen and lymph nodes of mice with EAE or following immunization. Analysis of TCRγδ gene usage in the CNS showed that the only TCRδ V gene families present in the CNS before EAE onset are from the DV7s6 and DV105s1 gene families. We also show that the primary IFN-γ-producing cells in the CNS are the encephalitogenic T cells, and that γδ T cell-deficient mice are unable to resolve EAE disease symptoms like control mice, thus exhibiting a long-term chronic disease course similar to that observed in IFN-γ-deficient mice. These data suggest that CNS resident γδ T cells promote the production of IFN-γ by encephalitogenic T cells in the CNS, which is ultimately required for the recovery from EAE.