bluuebunny/crossref_metadata_2025_split huggingface dataset:
Involvement of Lipopolysaccharide Binding Protein, CD14, and Toll-Like Receptors in the Initiation of Innate Immune Responses byTreponemaGlycolipids
Authors: Schröder Nicolas W. J. , Opitz Bastian , Lamping Norbert , Michelsen Kathrin S. , Zähringer Ulrich , Göbel Ulf B. , Schumann Ralf R. 
Published: April 2014

AbstractCulture supernatants from Treponema maltophilum associated with periodontitis in humans and Treponema brennaborense found in a bovine cattle disease accompanied with cachexia caused a dose-dependent TNF-α synthesis in human monocytes increasing with culture time. This activity could be reduced significantly by blocking the CD14-part of the LPS receptor using the My 4 mAb and by polymyxin B. In the murine macrophage cell line RAW 264.7, Treponema culture supernatants induced TNF-α secretion in a LPS binding protein (LBP)-dependent fashion. To enrich for active compounds, supernatants were extracted with butanol, while whole cells were extracted using a phenol/water method resulting in recovery of material exhibiting a similar activity profile. An LPS-LBP binding competition assay revealed an interaction of the treponeme phenol/water extracts with LBP, while precipitation studies implied an affinity to polymyxin B and endotoxin neutralizing protein. Macrophages obtained from C3H/HeJ mice carrying a Toll-like receptor (TLR)-4 mutation were stimulated with treponeme extracts for NO release to assess the role of TLRs in cell activation. Furthermore, NF-κB translocation in TLR-2-negative Chinese hamster ovary (CHO) cells was studied. We found that phenol/water-extracts of the two strains use TLRs differently with T. brennaborense-stimulating cells in a TLR-4-dependent fashion, while T. maltophilum-mediated activation apparently involved TLR-2. These results indicate the presence of a novel class of glycolipids in Treponema initiating inflammatory responses involving LBP, CD14, and TLRs.
Association of Deficient Type II Protein Kinase A Activity with Aberrant Nuclear Translocation of the RIIβ Subunit in Systemic Lupus Erythematosus T Lymphocytes
Authors: Mishra Nilamadhab , Khan Islam U. , Tsokos George C. , Kammer Gary M. 
Published: April 2014

AbstractSystemic lupus erythematosus (SLE) is an autoimmune disorder of indeterminate etiology characterized by abnormal T cell signal transduction and altered T cell effector functions. We have previously observed a profound deficiency of total protein kinase A (PKA) phosphotransferase activity in SLE T cells. Here we examined whether reduced total PKA activity in SLE T cells is in part the result of deficient type II PKA (PKA-II) isozyme activity. The mean PKA-II activity in SLE T cells was 61% of normal control T cells. The prevalence of deficient PKA-II activity in 35 SLE subjects was 37%. Deficient isozyme activity was persistent over time and was unrelated to SLE disease activity. Reduced PKA-II activity was associated with spontaneous dissociation of the cytosolic RIIβ2C2 holoenzyme and translocation of the regulatory (RIIβ) subunit from the cytosol to the nucleus. Confocal immunofluorescence microscopy revealed that the RIIβ subunit was present in ∼60% of SLE T cell nuclei compared with only 2–3% of normal and disease controls. Quantification of nuclear RIIβ subunit protein content by immunoprecipitation and immunoblotting demonstrated a 54% increase over normal T cell nuclei. Moreover, the RIIβ subunit was retained in SLE T cell nuclei, failed to relocate to the cytosol, and was associated with a persistent deficiency of PKA-II activity. In conclusion, we describe a novel mechanism of deficient PKA-II isozyme activity due to aberrant nuclear translocation of the RIIβ subunit and its retention in the nucleus in SLE T cells. Deficient PKA-II activity may contribute to impaired signaling in SLE T cells.
Adenoviral-Mediated Transfer of the TNF-Related Apoptosis-Inducing Ligand/Apo-2 Ligand Gene Induces Tumor Cell Apoptosis
Authors: Griffith Thomas S. , Anderson Richard D. , Davidson Beverly L. , Williams Richard D. , Ratliff Timothy L. 
Published: April 2014

AbstractTNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily of cytokines that induces apoptosis in a variety of cancer cells. The results presented in this study demonstrate that introduction of the human TRAIL gene into TRAIL-sensitive tumor cells using an adenoviral vector leads to the rapid production and expression of TRAIL protein, and subsequent death of the tumor cells. Tumor cell death was mediated by an apoptotic mechanism, as evidenced by the activation of caspase-8, cleavage of poly(ADP-ribose) polymerase, binding of annexin V, and inhibition by caspase inhibitor zVAD-fmk. These results define a novel method of using TRAIL as an antitumor therapeutic, and suggest the potential use for an adenovirus-encoding TRAIL as a method of gene therapy for numerous cancer types in vivo.
Cutting Edge: Lipid Raft Integrity Affects the Efficiency of MHC Class I Tetramer Binding and Cell Surface TCR Arrangement on CD8+ T Cells
Authors: Drake Donald R. , Braciale Thomas J. 
Published: April 2014

Abstract
Physically distinct cholesterol/sphingolipid-rich plasma membrane microdomains, so-called lipid rafts, have been recognized to play an important regulatory role in various cellular processes, from membrane trafficking to signal transduction, in a number of cell types. We report here that the ability of TCR on activated, functional CD8+ T lymphocytes to efficiently bind MHC class I tetramer complexes is dependent on the integrity of lipid rafts on the T lymphocyte membrane. We further provide evidence that TCR interact (associate) with lipid raft elements on the T cell surface before receptor engagement and that the topological arrangement of TCR on the cell surface is likewise influenced by lipid raft integrity.
Cutting Edge: IL-18-Transgenic Mice: In Vivo Evidence of a Broad Role for IL-18 in Modulating Immune Function
Authors: Hoshino Tomoaki , Kawase Yusuke , Okamoto Masaki , Yokota Koichi , Yoshino Kohichiro , Yamamura Ken-ichi , Miyazaki Jun-ichi , Young Howard A. , Oizumi Kotaro 
Published: April 2014

Abstract
IL-18 has been shown to be a strong cofactor for Th1 T cell development. However, we previously demonstrated that when IL-18 was combined with IL-2, there was a synergistic induction of a Th2 cytokine, IL-13, in both T and NK cells. More recently, we and other groups have reported that IL-18 can potentially induce IgE, IgG1, and Th2 cytokine production in murine experimental models. Here, we report on the generation of IL-18-transgenic (Tg) mice in which mature mouse IL-18 cDNA was expressed. CD8+CD44high T cells and macrophages were increased, but B cells were decreased in these mice while serum IgE, IgG1, IL-4, and IFN-γ levels were significantly increased. Splenic T cells in IL-18 Tg mice produced higher levels of IFN-γ, IL-4, IL-5, and IL-13 than control wild-type mice. Thus, aberrant expression of IL-18 in vivo results in the increased production of both Th1 and Th2 cytokines.
Neutrophil FcγRI as Target for Immunotherapy of Invasive Candidiasis
Authors: van Spriel Annemiek B. , van den Herik-Oudijk Ingrid E. , van de Winkel Jan G. J. 
Published: April 2014

Abstract
Invasive candidiasis represents a life-threatening disease for immunocompromised patients. This study focused on new immunotherapeutic approaches for systemic Candida albicans infections in a human FcγRI-transgenic mouse model. FcγRI (CD64) is a potent immunoactivating receptor on phagocytic and dendritic cells. In vivo targeting of C. albicans toward neutrophil-FcγRI by bispecific Abs and G-CSF effectively protected FcγRI-transgenic mice from lethal candidiasis. Nontransgenic mice were not protected, and treatment with bispecific Ab or G-CSF alone did not reduce mortality. Furthermore, infected FcγRI-transgenic mice developed high titers of anti-C. albicans IgG, and survival was extended on secondary infection without further treatment. These findings document the capacity of FcγRI to initiate potent anti-C. albicans immunity and support the development of FcγRI-directed immunotherapy of invasive fungal disease.
A Dual Role for TNF-α in Type 1 Diabetes: Islet-Specific Expression Abrogates the Ongoing Autoimmune Process When Induced Late but Not Early During Pathogenesis
Authors: Christen Urs , Wolfe Tom , Möhrle Ursula , Hughes Anna C. , Rodrigo Evelyn , Green E. Allison , Flavell Richard A. , von Herrath Matthias G. 
Published: April 2014

AbstractWe report here that islet-specific expression of TNF-α can play a dual role in autoimmune diabetes, depending on its precise timing in relation to the ongoing autoimmune process. In a transgenic model (rat insulin promoter-lymphocytic choriomeningitis virus) of virally induced diabetes, TNF-α enhanced disease incidence when induced through an islet-specific tetracycline-dependent promoter system early during pathogenesis. Blockade of TNF-α during this phase prevented diabetes completely, suggesting its pathogenetic importance early in disease development. In contrast, TNF-α expression abrogated the autoimmune process when induced late, which was associated with a reduction of autoreactive CD8 lymphocytes in islets and their lytic activities. Thus, the fine-tuned kinetics of an autoreactive process undergo distinct stages that respond in a differential way to the presence of TNF-α. This observation has importance for understanding the complex role of inflammatory cytokines in autoimmunity.
Infection of Human Macrophages and Dendritic Cells withMycobacterium tuberculosisInduces a Differential Cytokine Gene Expression That Modulates T Cell Response
Authors: Giacomini Elena , Iona Elisabetta , Ferroni Lucietta , Miettinen Minja , Fattorini Lanfranco , Orefici Graziella , Julkunen Ilkka , Coccia Eliana M. 
Published: April 2014

AbstractMacrophages and dendritic cells (DC) play an essential role in the initiation and maintenance of immune response to pathogens. To analyze early interactions between Mycobacterium tuberculosis (Mtb) and immune cells, human peripheral blood monocyte-derived macrophages (MDM) and monocyte-derived dendritic cells (MDDC) were infected with Mtb. Both cells were found to internalize the mycobacteria, resulting in the activation of MDM and maturation of MDDC as reflected by enhanced expression of several surface Ags. After Mtb infection, the proinflammatory cytokines TNF-α, IL-1, and IL-6 were secreted mainly by MDM. As regards the production of IFN-γ-inducing cytokines, IL-12 and IFN-α, was seen almost exclusively from infected MDDC, while IL-18 was secreted preferentially by macrophages. Moreover, Mtb-infected MDM also produce the immunosuppressive cytokine IL-10. Because IL-10 is a potent inhibitor of IL-12 synthesis from activated human mononuclear cells, we assessed the inhibitory potential of this cytokine using soluble IL-10R. Neutralization of IL-10 restored IL-12 secretion from Mtb-infected MDM. In line with these findings, supernatants from Mtb-infected MDDC induced IFN-γ production by T cells and enhanced IL-18R expression, whereas supernatants from MDM failed to do that. Neutralization of IFN-α, IL-12, and IL-18 activity in Mtb-infected MDDC supernatants by specific Abs suggested that IL-12 and, to a lesser extent, IFN-α and IL-18 play a significant role in enhancing IFN-γ synthesis by T cells. During Mtb infection, macrophages and DC may have different roles: macrophages secrete proinflammatory cytokines and induce granulomatous inflammatory response, whereas DC are primarily involved in inducing antimycobacterial T cell immune response.
Liver-Derived DEC205+B220+CD19− Dendritic Cells Regulate T Cell Responses
Authors: Lu Lina , Bonham C. Andrew , Liang Xiaoyan , Chen Zongyou , Li Wei , Wang Liangfu , Watkins Simon C. , Nalesnik Michael A. , Schlissel Mark S. , Demestris Anthony J. , Fung John J. , Qian Shiguang 
Published: April 2014

AbstractLeukocytes resident in the liver may play a role in immune responses. We describe a cell population propagated from mouse liver nonparenchymal cells in IL-3 and anti-CD40 mAb that exhibits a distinct surface immunophenotype and function in directing differentiation of naive allogeneic T cells. After culture, such cells are DEC-205brightB220+CD11c−CD19−, and negative for T (CD3, CD4, CD8α), NK (NK 1.1) cell markers, and myeloid Ags (CD11b, CD13, CD14). These liver-derived DEC205+B220+ CD19− cells have a morphology and migratory capacity similar to dendritic cells. Interestingly, they possess Ig gene rearrangements, but lack Ig molecule expression on the cell surface. They induce low thymidine uptake of allogeneic T cells in MLR due to extensive apoptosis of activated T cells. T cell proliferation is restored by addition of the common caspase inhibitor peptide, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk). T cells stimulated by liver-derived DEC205+B220+D19− cells release both IL-10 and IFN-γ, small amounts of TGF-β, and no IL-2 or IL-4, a cytokine profile resembling T regulatory type 1 cells. Expression of IL-10 and IFN-γ, but not bioactive IL-12 in liver DEC205+B220+CD19− cells was demonstrated by RNase protection assay. In vivo administration of liver DEC205+B220+CD19− cells significantly prolonged the survival of vascularized cardiac allografts in an alloantigen-specific manner.
Aspirin Inhibits In Vitro Maturation and In Vivo Immunostimulatory Function of Murine Myeloid Dendritic Cells
Authors: Hackstein Holger , Morelli Adrian E. , Larregina Adriana T. , Ganster Raymond W. , Papworth Glenn D. , Logar Alison J. , Watkins Simon C. , Falo Louis D. , Thomson Angus W. 
Published: April 2014

AbstractAspirin is the most commonly used analgesic and antiinflammatory agent. In this study, at physiological concentrations, it profoundly inhibited CD40, CD80, CD86, and MHC class II expression on murine, GM-CSF + IL-4 stimulated, bone marrow-derived myeloid dendritic cells (DC). CD11c and MHC class I expression were unaffected. The inhibitory action was dose dependent and was evident at concentrations higher than those necessary to inhibit PG synthesis. Experiments with indomethacin revealed that the effects of aspirin on DC maturation were cyclooxygenase independent. Nuclear extracts of purified, aspirin-treated DC revealed a decreased NF-κB DNA-binding activity, whereas Ab supershift analysis indicated that aspirin targeted primarily NF-κB p50. Unexpectedly, aspirin promoted the generation of CD11c+ DC, due to apparent suppression of granulocyte development. The morphological and ultrastructural appearance of aspirin-treated cells was consistent with immaturity. Aspirin-treated DC were highly efficient at Ag capture, via both mannose receptor-mediated endocytosis and macropinocytosis. By contrast, they were poor stimulators of naive allogeneic T cell proliferation and induced lower levels of IL-2 in responding T cells. They also exhibited impaired IL-12 expression and did not produce IL-10 after LPS stimulation. Assessment of the in vivo function of aspirin-treated DC, pulsed with the hapten trinitrobenzenesulfonic acid, revealed an inability to induce normal cell-mediated contact hypersensitivity, despite the ability of the cells to migrate to T cell areas of draining lymphoid tissue. These data provide new insight into the immunopharmacology of aspirin and suggest a novel approach to the manipulation of DC for therapeutic application.
TAP-Independent Presentation of CTL Epitopes by Trojan Antigens
Authors: Lu Jun , Wettstein Peter J. , Higashimoto Yuichiro , Appella Ettore , Celis Esteban 
Published: April 2014

AbstractThe majority of CTL epitopes are derived from intracellular proteins that are degraded in the cytoplasm by proteasomes into peptides that are transported into the endoplasmic reticulum by the TAP complex. These peptides can be further processed into the optimal size (8–10 residues) for binding with nascent MHC class I molecules, generating complexes that are exported to the cell surface. Proteins or peptides containing CTL epitopes can be introduced into the cytoplasm of APCs by linking them to membrane-translocating Trojan carriers allowing their incorporation into the MHC class I Ag-processing pathway. The present findings suggest that these “Trojan” Ags can be transported into the endoplasmic reticulum in a TAP-independent way where they are processed and trimmed into CTL epitopes. Furthermore, processing of Trojan Ags can also occur in the trans-Golgi compartment, with the participation of the endopeptidase furin and possibly with the additional participation of a carboxypeptidase. We believe that these findings will be of value for the design of CTL-inducing vaccines for the treatment or prevention of infectious and malignant diseases.
IFN-γ Alters the Pathology of Graft Rejection: Protection from Early Necrosis
Authors: Halloran Philip F. , Miller Leslie W. , Urmson Joan , Ramassar Vido , Zhu Lin-Fu , Kneteman Norman M. , Solez Kim , Afrouzian Marjan 
Published: April 2014

AbstractWe studied the effect of host IFN-γ on the pathology of acute rejection of vascularized mouse heart and kidney allografts. Organs from CBA donors (H-2k) were transplanted into BALB/c (H-2d) hosts with wild-type (WT) or disrupted (GKO, BALB/c mice with disrupted IFN-γ genes) IFN-γ genes. In WT hosts, rejecting hearts and kidneys showed mononuclear cell infiltration, intense induction of donor MHC products, but little parenchymal necrosis at day 7. Rejecting allografts in GKO recipients showed infiltrate but little or no induction of donor MHC and developed extensive necrosis despite patent large vessels. The necrosis was immunologically mediated, since it developed during rejection, was absent in isografts, and was prevented by immunosuppressing the recipient with cyclosporine or mycophenolate mofetil. Rejecting kidneys in GKO hosts showed increased mRNA for heme oxygenase 1, and decreased mRNA for NO synthase 2 and monokine inducible by IFN-γ (MIG). The mRNA levels for CTL genes (perforin, granzyme B, and Fas ligand) were similar in rejecting kidneys in WT and GKO hosts, and the host Ab responses were similar. The administration of recombinant IFN-γ to GKO hosts reduced but did not fully prevent the effects of IFN-γ deficiency: MHC was induced, but the prevention of necrosis and induction of MIG were incomplete compared with WT hosts. Thus, IFN-γ has unique effects in vascularized allografts, including induction of MHC and MIG, and protection against parenchymal necrosis, probably at the level of the microcirculation. This is probably a local action of IFN-γ produced in large quantities in the allograft.
Suppressors of Cytokine Signaling (SOCS)-1 and SOCS-3 Are Induced by CpG-DNA and Modulate Cytokine Responses in APCs
Authors: Dalpke Alexander H. , Opper Sandra , Zimmermann Stefan , Heeg Klaus 
Published: April 2014

AbstractDuring infection, the functional status of the innate immune system is tightly regulated. Although signals resulting in activation have been well characterized, counterregulative mechanisms are poorly understood. Suppressor of cytokine signaling (SOCS) proteins have been characterized as cytokine-inducible negative regulators of Janus kinase/STAT signaling in cells of hemopoietic origin. To analyze whether SOCS proteins could also be induced by pathogen-derived stimuli, we investigated the induction of SOCS-1 and SOCS-3 after triggering of macrophage cell lines, bone marrow-derived dendritic cells, and peritoneal macrophages with CpG-DNA. In this study, we show that CpG-DNA, but not GpC-DNA, induces expression of mRNA for SOCS-1 and SOCS-3 in vitro and in vivo. SOCS mRNA expression could be blocked by chloroquine and was independent of protein synthesis. Inhibitors of the mitogen-activated protein kinase pathway triggered by CpG-DNA were able to impede induction of SOCS mRNA. CpG-DNA triggered synthesis of SOCS proteins that could be detected by Western blotting. SOCS proteins were functional because they inhibited IFN-γ as well as IL-6- and GM-CSF-induced phosphorylation of STAT proteins. Furthermore, IFN-γ-induced up-regulation of MHC class II molecules was also prevented. The same effects could be achieved by overexpression of SOCS-1. Hence, the results indicate a substantial cross-talk between signal pathways within cells. They provide evidence for regulative mechanisms of Janus kinase/STAT signaling after triggering Toll-like receptor signal pathways.
Cloning and Characterization of IL-22 Binding Protein, a Natural Antagonist of IL-10-Related T Cell-Derived Inducible Factor/IL-22
Authors: Dumoutier Laure , Lejeune Diane , Colau Didier , Renauld Jean-Christophe 
Published: April 2014

Abstract
The class II cytokine receptor family includes the receptors for IFN-αβ, IFN-γ, IL-10, and IL-10-related T cell-derived inducible factor/IL-22. By screening genomic DNA databases, we identified a gene encoding a protein of 231 aa, showing 33 and 34% amino acid identity with the extracellular domains of the IL-22 receptor and of the IL-20R/cytokine receptor family 2-8, respectively, but lacking the transmembrane and cytoplasmic domains. A lower but significant sequence identity was found with other members of this family such as the IL-10R (29%), cytokine receptor family 2-4/IL-10Rβ (30%), tissue factor (26%), and the four IFN receptor chains (23–25%). This gene is located on chromosome 6q24, at 35 kb from the IFNGR1 gene, and is expressed in various tissues with maximal expression in breast, lungs, and colon. The recombinant protein was found to bind IL-10-related T cell-derived inducible factor/IL-22, and to inhibit the activity of this cytokine on hepatocytes and intestinal epithelial cells. We propose to name this natural cytokine antagonist IL-22BP for IL-22 binding protein.
Identification, Cloning, and Characterization of a Novel Soluble Receptor That Binds IL-22 and Neutralizes Its Activity
Authors: Kotenko Sergei V. , Izotova Lara S. , Mirochnitchenko Olga V. , Esterova Elena , Dickensheets Harold , Donnelly Raymond P. , Pestka Sidney 
Published: April 2014

Abstract
With the use of a partial sequence of the human genome, we identified a gene encoding a novel soluble receptor belonging to the class II cytokine receptor family. This gene is positioned on chromosome 6 in the vicinity of the IFNGR1 gene in a head-to-tail orientation. The gene consists of six exons and encodes a 231-aa protein with a 21-aa leader sequence. The secreted mature protein demonstrates 34% amino acid identity to the extracellular domain of the IL-22R1 chain. Cross-linking experiments demonstrate that the protein binds IL-22 and prevents binding of IL-22 to the functional cell surface IL-22R complex, which consists of two subunits, the IL-22R1 and the IL-10R2c chains. Moreover, this soluble receptor, designated IL-22-binding protein (BP), is capable of neutralizing IL-22 activity. In the presence of the IL-22BP, IL-22 is unable to induce Stat activation in IL-22-responsive human lung carcinoma A549 cells. IL-22BP also blocked induction of the suppressors of cytokine signaling-3 (SOCS-3) gene expression by IL-22 in HepG2 cells. To further evaluate IL-22BP action, we used hamster cells expressing a modified IL-22R complex consisting of the intact IL-10R2c and the chimeric IL-22R1/γR1 receptor in which the IL-22R1 intracellular domain was replaced with the IFN-γR1 intracellular domain. In these cells, IL-22 activates biological activities specific for IFN-γ, such as up-regulation of MHC class I Ag expression. The addition of IL-22BP neutralizes the ability of IL-22 to induce Stat activation and MHC class I Ag expression in these cells. Thus, the soluble receptor designated IL-22BP inhibits IL-22 activity by binding IL-22 and blocking its interaction with the cell surface IL-22R complex.