bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-12Rβ2 Promotes the Development of CD4+CD25+ Regulatory T Cells
Authors: Zhao Zhao , Yu Shuo , Fitzgerald Denise C. , Elbehi Mohamed , Ciric Bogoljub , Rostami A. M. , Zhang Guang-Xian 
Published: April 2014

Abstract
We have previously shown that mice lacking the IL-12-specific receptor subunit β2 (IL-12Rβ2) develop more severe experimental autoimmune encephalomyelitis than wild-type (WT) mice. The mechanism underlying this phenomenon is not known; nor is it known whether deficiency of IL-12Rβ2 impacts other autoimmune disorders similarly. In the present study we demonstrate that IL-12Rβ2−/− mice develop earlier onset and more severe disease in the streptozotocin-induced model of diabetes, indicating predisposition of IL-12Rβ2-deficient mice to autoimmune diseases. T cells from IL-12Rβ2−/− mice exhibited significantly higher proliferative responses upon TCR stimulation. The numbers of naturally occurring CD25+CD4+ regulatory T cells (Tregs) in the thymus and spleen of IL-12Rβ2−/− mice were comparable to those of WT mice. However, IL-12Rβ2−/− mice exhibited a significantly reduced capacity to develop Tregs upon stimulation with TGF-β, as shown by significantly lower numbers of CD25+CD4+ T cells that expressed Foxp3. Functionally, CD25+CD4+ Tregs derived from IL-12Rβ2−/− mice were less efficient than those from WT mice in suppressing effector T cells. The role of IL-12Rβ2 in the induction of Tregs was confirmed using small interfering RNA. These findings suggest that signaling via IL-12Rβ2 regulates both the number and functional maturity of Treg cells, which indicates a novel mechanism underlying the regulation of autoimmune diseases by the IL-12 pathway.
CD137 Induces Proliferation of Murine Hematopoietic Progenitor Cells and Differentiation to Macrophages
Authors: Jiang Dongsheng , Chen Yifeng , Schwarz Herbert 
Published: April 2014

AbstractCD137 is a member of the TNFR family, and reverse signaling through the CD137 ligand, which is expressed as a cell surface transmembrane protein, costimulates or activates APCs. CD137 and CD137 ligand are expressed on small subsets of bone marrow cells. Activation of bone marrow cells through CD137 ligand induces proliferation, colony formation and an increase in cell numbers. Compared with total bone marrow cells, the small subpopulation of progenitor cells that express no lineage markers but express CD117 cells (or Lin−, CD117+ cells) responds with the same activities to CD137 ligand signaling, but at a significantly enhanced rate. Concomitantly to proliferation, the cells differentiate to CFU granulocyte-macrophage and CFU macrophage, and then to monocytes and macrophages but not to granulocytes or dendritic cells. Hematopoietic progenitor cells differentiated in the presence of CD137 protein display enhanced phagocytic activity, secrete high levels of IL-10 but little IL-12 in response to LPS, and are incapable of stimulating T cell proliferation. These data demonstrate that reverse CD137 ligand signaling takes place in hematopoietic progenitor cells, in which it induces proliferation, an increase in cell numbers, colony formation, and differentiation toward monocytes and macrophages.
Editing Antigen Presentation: Antigen Transfer between Human B Lymphocytes and Macrophages Mediated by Class A Scavenger Receptors
Authors: Harvey Bohdan P. , Quan Timothy E. , Rudenga Benjamin J. , Roman Robert M. , Craft Joe , Mamula Mark J. 
Published: April 2014

Abstract
B lymphocytes can function independently as efficient APCs. However, our previous studies demonstrate that both dendritic cells and macrophages are necessary to propagate immune responses initiated by B cell APCs. This finding led us to identify a process in mice whereby Ag-specific B cells transfer Ag to other APCs. In this study, we report the ability and mechanism by which human B lymphocytes can transfer BCR-captured Ag to macrophages. The transfer of Ag involves direct contact between the two cells followed by the capture of B cell-derived membrane and/or intracellular components by the macrophage. These events are abrogated by blocking scavenger receptor A, a receptor involved in the exchange of membrane between APCs. Macrophages acquire greater amounts of Ag in the presence of specific B cells than in their absence. This mechanism allows B cells to amplify or edit the immune response to specific Ag by transferring BCR-captured Ag to other professional APCs, thereby increasing the frequency of its presentation. Ag transfer may perpetuate chronic autoimmune responses to specific self-proteins and help explain the efficacy of B cell-directed therapies in human disease.
Smallpox Inhibitor of Complement Enzymes (SPICE): Regulation of Complement Activation on Cells and Mechanism of Its Cellular Attachment
Authors: Liszewski M. Kathryn , Bertram Paula , Leung Marilyn K. , Hauhart Richard , Zhang Lijuan , Atkinson John P. 
Published: April 2014

Abstract
Despite eradication of smallpox three decades ago, public health concerns remain due to its potential use as a bioterrorist weapon. Smallpox and other orthopoxviruses express virulence factors that inhibit the host’s complement system. In this study, our goals were to characterize the ability of the smallpox inhibitor of complement enzymes, SPICE, to regulate human complement on the cell surface. We demonstrate that SPICE binds to a variety of cell types and that the heparan sulfate and chondroitin sulfate glycosaminoglycans serve as attachment sites. A transmembrane-engineered version as well as soluble recombinant SPICE inhibited complement activation at the C3 convertase step with equal or greater efficiency than that of the related host regulators. Moreover, SPICE attached to glycosaminoglycans was more efficient than transmembrane SPICE. We also demonstrate that this virulence activity of SPICE on cells could be blocked by a mAb to SPICE. These results provide insights related to the complement inhibitory activities of poxviral inhibitors of complement and describe a mAb with therapeutic potential.
High Mobility Group Protein-1 Inhibits Phagocytosis of Apoptotic Neutrophils through Binding to Phosphatidylserine
Authors: Liu Gang , Wang Jing , Park Young-Jun , Tsuruta Yuko , Lorne Emmanuel F. , Zhao Xia , Abraham Edward 
Published: April 2014

Abstract
Phagocytosis of apoptotic cells, also called efferocytosis, is an essential feature of immune responses and critical to resolution of inflammation. Impaired efferocytosis is associated with an unfavorable outcome from inflammatory diseases, including acute lung injury and pulmonary manifestations of cystic fibrosis. High mobility group protein-1 (HMGB1), a nuclear nonhistone DNA-binding protein, has recently been found to be secreted by immune cells upon stimulation with LPS and cytokines. Plasma and tissue levels of HMGB1 are elevated for prolonged periods in chronic and acute inflammatory conditions, including sepsis, rheumatoid arthritis, acute lung injury, burns, and hemorrhage. In this study, we found that HMGB1 inhibits phagocytosis of apoptotic neutrophils by macrophages in vivo and in vitro. Phosphatidylserine (PS) is directly involved in the inhibition of phagocytosis by HMGB1, as blockade of HMGB1 by PS eliminates the effects of HMGB1 on efferocytosis. Confocal and fluorescence resonance energy transfer demonstrate that HMGB1 interacts with PS on the neutrophil surface. However, HMGB1 does not inhibit PS-independent phagocytosis of viable neutrophils. Bronchoalveolar lavage fluid from Scnn+ mice, a murine model of cystic fibrosis lung disease which contains elevated concentrations of HMGB1, inhibits neutrophil efferocytosis. Anti-HMGB1 Abs reverse the inhibitory effect of Scnn+ bronchoalveolar lavage on efferocytosis, showing that this effect is due to HMGB1. These findings demonstrate that HMGB1 can modulate phagocytosis of apoptotic neutrophils and suggest an alternative mechanism by which HMGB1 is involved in enhancing inflammatory responses.
Inhibition of Arginase Activity Enhances Inflammation in Mice with Allergic Airway Disease, in Association with Increases in Protein S-Nitrosylation and Tyrosine Nitration
Authors: Ckless Karina , Lampert Anniek , Reiss Jessica , Kasahara David , Poynter Matthew E. , Irvin Charles G. , Lundblad Lennart K. A. , Norton Ryan , van der Vliet Albert , Janssen-Heininger Yvonne M. W. 
Published: April 2014

Abstract
Pulmonary inflammation in asthma is orchestrated by the activity of NF-κB. NO and NO synthase (NOS) activity are important modulators of inflammation. The availability of the NOS substrate, l-arginine, is one of the mechanisms that controls the activity of NOS. Arginase also uses l-arginine as its substrate, and arginase-1 expression is highly induced in a murine model of asthma. Because we have previously described that arginase affects NOx content and interferes with the activation of NF-κB in lung epithelial cells, the goal of this study was to investigate the impact of arginase inhibition on the bioavailability of NO and the implications for NF-κB activation and inflammation in a mouse model of allergic airway disease. Administration of the arginase inhibitor BEC (S-(2-boronoethyl)-l-cysteine) decreased arginase activity and caused alterations in NO homeostasis, which were reflected by increases in S-nitrosylated and nitrated proteins in the lungs from inflamed mice. In contrast to our expectations, BEC enhanced perivascular and peribronchiolar lung inflammation, mucus metaplasia, NF-κB DNA binding, and mRNA expression of the NF-κB-driven chemokine genes CCL20 and KC, and lead to further increases in airways hyperresponsiveness. These results suggest that inhibition of arginase activity enhanced a variety of parameters relevant to allergic airways disease, possibly by altering NO homeostasis.
Unique Properties of the Chicken TLR4/MD-2 Complex: Selective Lipopolysaccharide Activation of the MyD88-Dependent Pathway
Authors: Keestra A. Marijke , van Putten Jos P. M. 
Published: April 2014

Abstract
During evolution, mammals have evolved a powerful innate immune response to LPS. Chickens are much more resistant to LPS-induced septic shock. Herein we report that chickens sense LPS via orthologs of mammalian TLR4 and myeloid differentiation protein-2 (MD-2) rather than the previously implicated chicken TLR2 isoform type 2 (chTLR2t2) receptor. Cloning and expression of recombinant chTLR4 and chMD-2 in HeLa 57A cells activated NF-κB at concentrations of LPS as low as 100 pg/ml. Differential pairing of chicken and mammalian TLR4 and MD-2 indicated that the protein interaction was species-specific in contrast to the formation of functional human and murine chimeric complexes. The chicken LPS receptor responded to a wide variety of LPS derivatives and to the synthetic lipid A compounds 406 and 506. The LPS specificity resembled the functionality of the murine rather than the human TLR4/MD-2 complex. Polymorphism in chTLR4 (Tyr383His and Gln611Arg) did not influence the LPS response. Interestingly, LPS consistently failed to activate the MyD88-independent induction of IFN-β in chicken cells, in contrast to the TLR3 agonist poly(I:C) that yielded a potent IFN-β response. These results suggest that chicken lack a functional LPS-specific TRAM-TRIF (TRIF-related adapter molecule/TIR-domain-containing adapter-inducing IFN-β) signaling pathway, which may explain their aberrant response to LPS compared with the mammalian species.
4-1BB Enhances Proliferation of Beryllium-Specific T Cells in the Lung of Subjects with Chronic Beryllium Disease
Authors: Mack Douglas G. , Lanham Allison K. , Palmer Brent E. , Maier Lisa A. , Watts Tania H. , Fontenot Andrew P. 
Published: April 2014

Abstract
In contrast to naive T cells, reactivation of memory cells is less dependent on CD28-mediated costimulation. We have shown that circulating beryllium-specific CD4+ T cells from chronic beryllium disease patients remain CD28-dependent, while those present in the lung no longer require CD28 for T cell activation. In the present study, we analyzed whether other costimulatory molecules are essential for beryllium-induced T cell function in the lung. Enhanced proliferation of a beryllium-responsive, HLA-DP2-restricted T cell line was seen after the induction of 4-1BB ligand expression on the surface of HLA-DP2-expressing fibroblasts. Following beryllium exposure, CD4+ T cells from blood and bronchoalveolar lavage of chronic beryllium disease patients up-regulate 4-1BB expression, and the majority of beryllium-responsive, IFN-γ-producing CD4+ T cells in blood coexpress CD28 and 4-1BB. Conversely, a significant fraction of IFN-γ-producing bronchoalveolar lavage (BAL) T cells express 4-1BB in the absence of CD28. In contrast to blood, inhibition of the 4-1BB ligand-4-1BB interaction partially blocked beryllium-induced proliferation of BAL CD4+ T cells, and a lack of 4-1BB expression on BAL T cells was associated with increased beryllium-induced cell death. Taken together, these findings suggest an important role of 4-1BB in the costimulation of beryllium-responsive CD4+ T cells in the target organ.
Cutting Edge: The Mechanism of Invariant NKT Cell Responses to Viral Danger Signals
Authors: Tyznik Aaron J. , Tupin Emmanuel , Nagarajan Niranjana A. , Her Min J. , Benedict Chris A. , Kronenberg Mitchell 
Published: April 2014

Abstract
Invariant NK T (iNKT) cells influence the response to viral infections, although the mechanisms are poorly defined. In this study we show that these innate-like lymphocytes secrete IFN-γ upon culture with CpG oligodeoxynucleotide-stimulated dendritic cells (DCs) from mouse bone marrow. This requires TLR9 signaling and IL-12 secretion by the activated DCs, but it does not require CD1d expression. iNKT cells also produce IFN-γ in response to mouse CMV infection. Their mechanism of mouse CMV detection is quite similar to that of CpG, requiring both TLR9 signaling and IL-12 secretion, while the need for CD1d expression is relatively minor. Consequently, iNKT cells have the ability to respond to a variety of microbes, including viruses, in an Ag-independent manner, suggesting they may play a broad role in antipathogen defenses despite their limited TCR repertoire.
IFN-γ-Induced TNF-α Expression Is Regulated by Interferon Regulatory Factors 1 and 8 in Mouse Macrophages
Authors: Vila-del Sol Virginia , Punzón Carmen , Fresno Manuel 
Published: April 2014

Abstract
We have previously described that IFN-γ induces cyclooxygenase 2 and inducible NO synthase expression by a mechanism that involved endogenously produced TNF-α. In this study, we report that TNF-α production is induced by IFN-γ treatment in the murine macrophage cell line RAW 264.7. TNF-α mRNA levels are increased in cells treated with IFN-γ in a time-dependent manner and IFN-γ also increased human TNF-α promoter-dependent transcription. Two regions in the TNF-α promoter seem to be responsible for the IFN-γ response: a distal region between −1311 and −615 bp of the human TNF-α promoter, and a proximal region located between −95 and −36 bp upstream of the transcriptional start. In contrast, IFN-γ stimulation induces the expression of the transcription factors IRF-1 and IRF-8. Overexpression of these transcription factors produces an increase in the transcriptional activity of the human TNF-α promoter. There is a correlation between the regions of the TNF-α promoter responsible of the transcriptional activation elicited by IRF-1 and IRF-8 and those required for IFN-γ response. In addition, IRF-1 and IRF-8 are recruited to the TNF-α promoter in IFN-γ-treated RAW 264.7 cells, as demonstrated by chromatin immunoprecipitation assays. Moreover, overexpression of IRF-1 and IRF-8 induces TNF-α production in unstimulated RAW 264.7 macrophages, comparable to the production of TNF-α elicited by IFN-γ stimulation, and silencing of IRF-1 and/or IRF-8 with specific small interfering RNAs, decreases IFN-γ-elicited TNF-α production. In summary, IFN-γ treatment induces TNF-α expression at transcriptional level requiring the coordinate action of IRF-1 and IRF-8.
Activation of Nonclassical CD1d-Restricted NK T Cells Induces Airway Hyperreactivity in β2-Microglobulin-Deficient Mice
Authors: Koh Youngil I. , Kim Hye Young , Meyer Everett H. , Pichavant Muriel , Akbari Omid , Yasumi Takahiro , Savage Paul B. , DeKruyff Rosemarie H. , Umetsu Dale T. 
Published: April 2014

Abstract
Allergic asthma is characterized by Th2-driven eosinophilic airway inflammation and by a central feature called airway hyperreactivity (AHR), development of which requires the presence of classical type I invariant NK T (iNKT) cells. Allergen-induced AHR, however, develops in β2-microglobulin (β2m)−/− mice, which lack classical iNKT cells, suggesting that in some situations iNKT cells may be dispensable for the development of AHR. In contrast, our studies now suggest that a CD1d-restricted, NK1.1+ noninvariant TCR NKT cell population is present in β2m−/− mice and is responsible for the development of AHR but not for Th2 responses. Furthermore, treatment of β2m−/− mice with anti-CD1d mAb or anti-NK1.1 mAb unexpectedly abolished allergen-induced AHR. The CD1-restricted NKT cells in these mice, which failed to respond to α-galactosylceramide and which therefore were not classical type I iNKT cells, appear to represent an NKT cell subset restricted by a β2m-independent form of CD1d. These results indicate that, although classical type I iNKT cells are normally required for the development of AHR, under different circumstances other NKT cell subsets, including nonclassical NKT cells, may substitute for classical iNKT cells and induce AHR.
Galectin-1 Promotes Immunoglobulin Production during Plasma Cell Differentiation
Authors: Tsai Chih-Ming , Chiu Yi-Kai , Hsu Tsui-Ling , Lin I-Ying , Hsieh Shie-Liang , Lin Kuo-I 
Published: April 2014

Abstract
Galectin-1, a β-galactoside-binding soluble lectin, has been implicated in regulating immune system homeostasis. We investigated the function of galectin-1 in plasma cell differentiation and found that it is induced in primary murine and human differentiating B cells. B lymphocyte-induced maturation protein-1 (Blimp-1), a master regulator for plasma cell differentiation, was necessary and sufficient to induce galectin-1 expression. Notably, ectopic expression of galectin-1 in mature B cells increased Ig μ-chain transcript levels as well as the overall level of Ig production. This function of galectin-1 was dependent on binding to cell surface glycosylated counter receptors, as a galectin-1 mutant deficient in β-galactoside binding showed diminished ability to promote Ig production. Extracellular galectin-1 bound more significantly to mature B cells than to plasma cells. Lastly, we found that the sugar compound N-acetyllactosamine blocked the binding of galectin-1 to murine splenic B cells and inhibited their differentiation. Taken together, these data are the first to demonstrate a role for galectin-1 in promoting Ig production during plasma cell differentiation.
Nicotinamide Phosphoribosyl Transferase/Pre-B Cell Colony-Enhancing Factor/Visfatin Is Required for Lymphocyte Development and Cellular Resistance to Genotoxic Stress
Authors: Rongvaux Anthony , Galli Mara , Denanglaire Sébastien , Van Gool Frédéric , Drèze Pierre L. , Szpirer Claude , Bureau Fabrice , Andris Fabienne , Leo Oberdan 
Published: April 2014

Abstract
Nicotinamide phosphoribosyl transferase (Nampt)/pre-B cell colony-enhancing factor (PBEF)/visfatin is a protein displaying multiple functional properties. Originally described as a cytokine-like protein able to regulate B cell development, apoptosis, and glucose metabolism, this protein also plays an important role in NAD biosynthesis. To gain insight into its physiological role, we have generated a mouse strain expressing a conditional Nampt allele. Lack of Nampt expression strongly affects development of both T and B lymphocytes. Analysis of hemizygous cells and in vitro cell lines expressing distinct levels of Nampt illustrates the critical role of this protein in regulating intracellular NAD levels. Consequently, a clear relationship was found between intracellular Nampt levels and cell death in response to the genotoxic agent MNNG (N-methyl-N′-nitro-N-nitrosoguanidine), confirming that this enzyme represents a key regulator of cell sensitivity to NAD-consuming stress secondary to poly(ADP-ribose) polymerases overactivation. By using mutant forms of this protein and a well-characterized pharmacological inhibitor (FK866), we unequivocally demonstrate that the ability of the Nampt to regulate cell viability during genotoxic stress requires its enzymatic activity. Collectively, these data demonstrate that Nampt participates in cellular resistance to genotoxic/oxidative stress, and it may confer to cells of the immune system the ability to survive during stressful situations such as inflammation.
Inhibitory Immunoglobulin-Like Receptors LILRB and PIR-B Negatively Regulate Osteoclast Development
Authors: Mori Yu , Tsuji Sukenao , Inui Masanori , Sakamoto Yuzuru , Endo Shota , Ito Yumi , Fujimura Shion , Koga Takako , Nakamura Akira , Takayanagi Hiroshi , Itoi Eiji , Takai Toshiyuki 
Published: April 2014

Abstract
Osteoclasts, multinucleated cells of myeloid-monocytic origin, are responsible for bone resorption, which is crucial for maintenance of bone homeostasis in concert with bone-forming osteoblasts of nonhematopoietic, mesenchymal origin. Receptor activator of NF-κB ligand (RANKL) and M-CSF, expressed on the surface of and secreted by osteoblasts, respectively, are essential factors that facilitate osteoclast formation. In contrast to the activation processes for osteoclast formation, inhibitory mechanisms for it are poorly understood. Herein we demonstrate that inhibitory Ig-like receptors recruiting Src homology 2 domain-containing tyrosine phosphatase 1 (SHP-1) are expressed on osteoclast precursor cells like other myeloid cells, and that they play a regulatory role in the development of osteoclasts. We detected cell-surface expression of paired Ig-like receptor (PIR)-B and four isoforms of leukocyte Ig-like receptor (LILR)B on cultured osteoclast precursor cells of mouse and human origin, respectively, and showed that all of these ITIM-harboring inhibitory receptors constitutively recruit SHP-1 in the presence of RANKL and M-CSF, and that some of them can suppress osteoclast development in vitro. Fluorescence energy transfer analyses have suggested that the constitutive binding of either murine PIR-B or its human ortholog LILRB1 to MHC class I molecules on the same cell surface comprises one of the mechanisms for developmental regulation. These results constitute the first evidence of the regulation of osteoclast formation by cell-surface, ITIM-harboring Ig-like receptors. Modulation of these regulatory receptors may be a novel way to control various skeletal system disorders and inflammatory arthritis.