bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of Lipopolysaccharide Sensitivity by IFN Regulatory Factor-2
Authors: Cuesta Natalia , Salkowski Cindy A. , Thomas Karen E. , Vogel Stefanie N. 
Published: April 2014

AbstractIFN regulatory factors (IRFs) are a family of transcription factors and include several members that regulate expression of pro- and anti-inflammatory genes. Mice with a targeted mutation in IRF-2 (IRF-2−/−) were studied after injection of LPS to evaluate the importance of IRF-2 in the regulation of endotoxicity. IRF-2−/− mice were highly refractory to LPS-induced lethality. Although hepatic TNF-α mRNA and circulating TNF-α were significantly elevated in LPS-challenged IRF-2−/− mice, levels of IL-1, IL-12, and IFN-γ mRNA and protein, as well as IL-6 protein, were significantly lower than levels seen in LPS-challenged IRF-2+/+ mice. IRF-2−/− mice were also more refractory to TNF-α challenge than were control mice, which was consistent with their diminished sensitivity to LPS, yet no significant difference in the mRNA expression of TNFRs was observed. IL-12Rβ2 mRNA levels from LPS-challenged IRF-2−/− mice were significantly different after 1, 6, and 8 h, suggesting that both diminished IL-12 and altered IL-12R expression contribute to the paucity of IFN-γ produced. IRF-2 knockout mice also failed to sustain LPS-inducible levels of IRF-1 and IFN consensus sequence binding protein mRNA expression, two transacting factors required for IL-12 transcription, perhaps as a result of diminished IL-1β, IL-6, and IFN-γ levels. Liver sections from IRF-2+/+ and IRF-2−/− mice were analyzed 6 h after a typically lethal injection of LPS. IRF-2−/− mice exhibited greater numbers of apoptotic Kupffer cells than did wild-type mice, suggesting a novel anti-apoptotic role for IRF-2. Collectively, these findings reveal a critical role for IRF-2 in endotoxicity, and point to a previously unappreciated role for IRF-2 in the regulation of apoptosis.
Expression of a Novel Murine Type I IFN in the Pancreatic Islets Induces Diabetes in Mice
Authors: Vassileva Galya , Chen Shu-Cheng , Zeng Ming , Abbondanzo Susan , Jensen Kristian , Gorman Daniel , Baroudy Bahige M. , Jiang Ying , Murgolo Nicholas , Lira Sergio A. 
Published: April 2014

Abstract
IFN-κ belongs to a recently identified subclass of type I IFNs. In this study, we report the cloning and preliminary characterization of the murine homologue of IFN-κ. The gene encodes a 200-aa protein which is 38.5% homologous to human IFN-κ. Murine IFN-κ contains four cysteines in analogous positions to those observed in the IFN-α and an additional fifth unique cysteine, C174. The murine gene is located on chromosome 4, where other type I murine IFN genes, IFN-α and IFN-β, are clustered. This region is syntenic with human chromosome 9 where the gene encoding IFN-κ and the type I IFN gene cluster are found. Mouse IFN-κ is expressed at low levels in peritoneal macrophages and its expression is up-regulated by dsRNA and IFN-γ. Similar to previously reported transgenic mice carrying type I and type II IFNs, transgenic mice overexpressing murine IFN-κ in the β cells of the pancreas develop overt diabetes with hyperglycemia. Histological characterization of pancreatic islets from these transgenic mice showed inflammatory infiltrates with corresponding destruction of β cells.
Complement C5a Receptor-Mediated Signaling May Be Involved in Neurodegeneration in Alzheimer’s Disease
Authors: Farkas Imre , Takahashi Mitsuo , Fukuda Atsuo , Yamamoto Naoki , Akatsu Hiroyasu , Baranyi Lajos , Tateyama Hisashi , Yamamoto Takayuki , Okada Noriko , Okada Hidechika 
Published: April 2014

AbstractIn our earlier results, we demonstrated that cells expressing the complement C5aR are vulnerable since abnormal activation of C5aR caused apoptosis of these cells. In this study, we demonstrate that activation of C5aR by antisense homology box (AHB) peptides synthesized in multiple antigenic peptide form and representing putative interaction sites of the C5a/C5aR evoked calcium influx in TGW neuroblastoma cells. Dose-dependent inhibition of the response was found when the cells were pretreated with C5a, suggesting that C5aR was involved in this process. In addition, pretreatment with monomeric forms of the AHB peptides resulted in attenuation of the calcium signals, supporting the idea of the role of C5aR in this process. Cells of a neuron-rich primary culture and pyramidal cells of rat brain slices also responded to the AHB peptide activation with an increase in the intracellular calcium level, showing that calcium metabolism might be affected in these cells. TUNEL staining demonstrated that C5aR-mediated apoptosis could be induced both in cells of the primary culture as well as in cortical pyramidal neurons of the rat brain. In addition, we investigated expression of C5aR in the hippocampal and cortical neurons of human brains of healthy and demented patients using two anti-human C5aR Abs. Pyramidal cells of the hippocampus and cortex and granular cells of the hippocampus were immunopositive on staining. Although staining was also positive in the vascular dementia brain, it disappeared in the brain with Alzheimer’s disease. These results provide further support that C5aR may be involved in neurodegeneration.
Impaired Secretion of IL-10 by T Cells from Patients with Common Variable Immunodeficiency–Involvement of Protein Kinase A Type I
Authors: Holm Are Martin , Aukrust Pål , Aandahl Einar Martin , Müller Fredrik , Taskén Kjetil , Frøland Stig S. 
Published: April 2014

Abstract
Common variable immunodeficiency (CVID) is a heterogeneous group of B cell deficiency syndromes. T cell abnormalities are present in a high proportion of patients with CVID, suggesting impaired T cell-mediated stimulation of B cells. Based on the importance of IL-10 for B cell function and the involvement of the cAMP/protein kinase A type I (PKAI) system in IL-10 synthesis, we examined IL-10 secretion in T cells from CVID patients and controls, particularly focusing on possible modulatory effects of the cAMP/PKAI system. Our main findings were: 1) anti-CD3 and anti-CD3/anti-CD28 activated T cells from CVID patients secreted less IL-10 than healthy controls. This defect was not related to varying proportions of T cell subsets (e.g., CD4+/CD8+, CD45RA+/RO+, or CD28− T cells); 2) PKAI activation through the cAMP agonist 8-CPT-cAMP markedly inhibited IL-10 secretion from T cells through CD3 and CD28 activation in both patients and controls, but the sensitivity for cAMP-dependent inhibition was increased in CVID; 3) selective PKAI inhibition by Rp-8-Br-cAMPS markedly increased IL-10 secretion in anti-CD3 and anti-CD3/anti-CD28-stimulated T cells in both patients and controls. Even at the lowest concentrations of Rp-8-Br-cAMPS, IL-10 secretion in CVID patients reached levels comparable to those in controls. Our findings suggest impaired secretion of IL-10 by T cells from CVID patients, suggesting a possible link between T cell deficiency and impaired B cell function in CVID. The involvement of the cAMP/PKAI system in this defect suggests a novel target for therapeutic immunomodulation in CVID.
Retinoic Acid Reduces Autoimmune Renal Injury and Increases Survival in NZB/W F1 Mice
Authors: Kinoshita Koji , Yoo Byun-Suk , Nozaki Yuji , Sugiyama Masafumi , Ikoma Shinya , Ohno Motoki , Funauchi Masanori , Kanamaru Akihisa 
Published: April 2014

Abstract
Retinoic acids, a group of natural and synthetic vitamin A derivatives, have potent antiproliferative and anti-inflammatory properties. Recently, retinoic acids were reported to inhibit Th1 cytokine production. We investigated the effects of retinoic acid on lupus nephritis in a model of NZB/NZW F1 (NZB/W F1) mice. Three-month-old NZB/W F1 mice were separated into two groups: one treated with all-trans-retinoic acid (ATRA; 0.5 mg i.p., three times weekly for 7 mo) and one with saline as a control. Compared with controls, ATRA-treated mice survived longer and exhibited a significant reduction of proteinuria, renal pathological findings including glomerular IgG deposits, and serum anti-DNA Abs. Splenomegaly was less marked in the treated mice than in controls. Transcripts encoding IFN-γ, IL-2, and IL-10 in splenic CD4+ T cells were significantly reduced in treated mice compared with controls. We conclude that treatment with ATRA in SLE-prone NZB/W F1 mice significantly alleviates autoimmune renal disorder and prolongs survival; this may thus represent a novel approach to the treatment of patients with lupus nephritis.
Proliferation and Survival of Activated B Cells Requires Sustained Antigen Receptor Engagement and Phosphoinositide 3-Kinase Activation
Authors: Donahue Amber C. , Fruman David A. 
Published: April 2014

AbstractIn this study, we investigate the extracellular and intracellular signals that drive cell cycle progression of activated B cells in the absence of T cell help. We find that brief engagement of the B cell receptor is sufficient to induce a single cell division in a fraction of cells, but that survival during successive cell divisions requires sustained receptor stimulation. In contrast, T cells have been shown previously to commit to multiple cell divisions following brief TCR engagement. Both early and late B cell receptor signals are blocked by inhibitors of phosphoinositide 3-kinase and mammalian target of rapamycin and are associated with S6 kinase activation and increased cell size. The requirement for ongoing Ag receptor signaling can be overcome by engagement of CD40 but only partially by IL-4. Proliferation driven by LPS also requires sustained exposure to the stimulus. These findings reveal checkpoints that may limit T-independent B cell responses when Ag exposure is transient.
Aod1Controlling Day 3 Thymectomy-Induced Autoimmune Ovarian Dysgenesis in Mice Encompasses Two Linked Quantitative Trait Loci with Opposing Allelic Effects on Disease Susceptibility
Authors: Roper Randall J. , McAllister Ryan D. , Biggins Julia E. , Michael Sandra D. , Min Soo Hong , Tung Kenneth S. K. , Call Stanford B. , Gao Jianfeng , Teuscher Cory 
Published: April 2014

AbstractDay 3 thymectomy (D3Tx) leads to a paucity of CD4+CD25+ suppressor T cells, a loss of peripheral tolerance, and the development of organ-specific autoimmune disease in adult mice. Importantly, D3Tx does not lead to autoimmune disease in all mouse strains, indicating that this process is genetically controlled. Previously, we reported linkage of D3Tx-induced autoimmune ovarian dysgenesis (AOD) and its intermediate phenotypes, antiovarian autoantibody responsiveness, oophoritis, and atrophy, to five quantitative trait loci (QTL), designated Aod1 through Aod5. We also showed interaction between these QTL and H2 as well as Gasa2, a QTL controlling susceptibility to D3Tx-induced autoimmune gastritis. To physically map Aod1, interval-specific bidirectional recombinant congenic strains of mice were generated and studied for susceptibility to D3Tx-induced AOD. Congenic mapping studies revealed that Aod1 controls susceptibility to oophoritis and comprises two linked QTL with opposing allelic effects. Aod1a resides between D16Mit211 (23.3 cM) and D16Mit51 (66.75 cM) on chromosome 16. Aod1b maps proximal of Aod1a between D16Mit89 (20.9 cM) and D16Mit211 (23.3 cM) and includes the candidate genes stefin A1, A2, and A3 (Stfa1-Stfa3), inhibitors of cathepsin S, a cysteine protease required for autoantigen presentation, and the development of autoimmune disease of the salivary and lacrimal glands following D3Tx. cDNA sequencing revealed the existence of structural polymorphisms for both Stfa1 and Stfa2. Given the roles of cathepsins in Ag processing and presentation, Stfa1 and Stfa2 alleles have the potential to control susceptibility to autoimmune disease at the level of both CD4+CD25+ suppressor and CD4+CD25− effector T cells.
B Cells Activated by Lipopolysaccharide, But Not By Anti-Ig and Anti-CD40 Antibody, Induce Anergy in CD8+ T Cells: Role of TGF-β1
Authors: Parekh Vrajesh V. , Prasad Durbaka V. R. , Banerjee Pinaki P. , Joshi Bimba N. , Kumar Anil , Mishra Gyan C. 
Published: April 2014

AbstractB cells recognize Ag through their surface IgRs and present it in the context of MHC class II molecules to CD4+ T cells. Recent evidence indicates that B cells also present exogenous Ags in the context of MHC class I to CD8+ T cells and thus may play an important role in the modulation of CTL responses. However, in this regard, conflicting reports are available. One group of studies suggests that the interaction between B cells and CD8+ T cells leads to the activation of the T cells, whereas other studies propose that it induces T cell tolerance. For discerning this dichotomy, we used B cells that were activated with either LPS or anti-Ig plus anti-CD40 Ab, which mimic the T-independent and T-dependent modes of B cell activation, respectively, to provide accessory signals to resting CD8+ T cells. Our results show that, in comparison with anti-Ig plus anti-CD40 Ab-activated B cells, the LPS-activated B cells (LPS-B) failed to induce significant levels of proliferation, cytokine secretion, and cytotoxic ability of CD8+ T cells. This hyporesponsiveness of CD8+ T cells activated with LPS-B was significantly rescued by anti-TGF-β1 Ab. Moreover, it was found that such hyporesponsive CD8+ T cells activated with LPS-B had entered a state of anergy. Furthermore, LPS-B expresses a significantly higher level of TGF-β1 on the surface, which caused the observed hyporesponsiveness of CD8+ T cells. Therefore, this study, for the first time, provides a novel mechanism of B cell surface TGF-β1-mediated hyporesponsiveness leading to anergy of CD8+ T cells.
Pathogenesis of Autoimmunity After Xenogeneic Thymus Transplantation
Authors: Yan Yehong , Devos Timothy , Yu Lisong , Xia Guliang , Rutgeerts Omer , Goebels Jozef , Segers Constant , Lin Yuan , Vandeputte Michel , Waer Mark 
Published: April 2014

AbstractThymus transplantation is a promising strategy to induce xenotolerance, but may also induce an autoimmune syndrome (AIS). The pathogenesis of this AIS was explored using nude rats as recipients. Thymus grafts consisted of fetal hamster thymic tissue with or without mixing with fetal rat tissue such as thymus, thyroid, salivary gland, and heart. All hamster thymus recipients died of AIS within 2–3 mo. In most recipients of xenothymus mixed with rat tissues such as thymus, thyroid, and salivary gland, but not heart, AIS was prevented, indicating an insufficient presence of rat epithelial cell Ags within the xenothymus. AIS could be transferred to control nude rats by whole splenocytes or by splenocyte subpopulations such as CD3+, CD3−, and B lymphocytes, but not by non-T, non-B cells from AIS animals. This transfer could be suppressed by cotransferring either CD4+ or CD8+ lymphocytes from euthymic rats, but not by splenocytes from recipients of syngeneic or xenogeneic thymus mixed with rat tissue, indicating a defective generation of regulatory lymphocytes. As for CD4+ regulatory cells this defect was probably qualitative, because the percentages of CD4+CD25+ or CD4+CD45RClow populations were normal after xenothymus transplantation. As for the CD8+ regulatory cells, the defect was quantitative, as CD8+ cell levels always remained low. The latter was related to the nonvascularized nature of thymus grafts. In conclusion, AIS after xenothymus transplantation in nude rats is due to a combination of insufficient intrathymic presence of host-type epithelial cell Ags and a defective generation of regulatory T lymphocytes.
TCR Dynamics in Human Mature T Lymphocytes Lacking CD3γ
Authors: Torres Pilar S. , Alcover Andrés , Zapata David A. , Arnaud Jacques , Pacheco Alberto , Martín-Fernández José M. , Villasevil Eugenia M. , Sanal Ozden , Regueiro José R. 
Published: April 2014

AbstractThe contribution of CD3γ to the surface expression, internalization, and intracellular trafficking of the TCR/CD3 complex (TCR) has not been completely defined. However, CD3γ is believed to be crucial for constitutive as well as for phorbol ester-induced internalization. We have explored TCR dynamics in resting and stimulated mature T lymphocytes derived from two unrelated human congenital CD3γ-deficient (γ−) individuals. In contrast to γ− mutants of the human T cell line Jurkat, which were selected for their lack of membrane TCR and are therefore constitutively surface TCR negative, these natural γ− T cells constitutively expressed surface TCR, mainly through biosynthesis of new chains other than CD3γ. However, surface (but not intracellular) TCR expression in these cells was less than wild-type cells, and normal surface expression was clearly CD3γ-dependent, as it was restored by retroviral transduction of CD3γ. The reduced surface TCR expression was likely caused by an impaired assembly or membrane transport step during recycling, whereas constitutive internalization and degradation were apparently normal. Ab binding to the mutant TCR, but not phorbol ester treatment, caused its down-modulation from the cell surface, albeit at a slower rate than in normal controls. Kinetic confocal analysis indicated that early ligand-induced endocytosis was impaired. After its complete down-modulation, TCR re-expression was also delayed. The results suggest that CD3γ contributes to, but is not absolutely required for, the regulation of TCR trafficking in resting and Ag-stimulated mature T lymphocytes. The results also indicate that TCR internalization is regulated differently in each case.
Alterations in Fas Expression Are Characteristic of, But Not Solely Responsible for, Enhanced Metastatic Competence
Authors: Liu Kebin , Abrams Scott I. 
Published: April 2014

Abstract
Dysregulation of the Fas pathway has been implicated in tumor progression; however, how alterations in Fas expression influence metastatic behavior remains unresolved. In this study, we investigated the link between Fas expression and metastatic capacity in two mouse tumor models: one was a sarcoma, which was used to analyze the consequences of loss of Fas function in experimental pulmonary metastases, and the other was a mammary carcinoma, where Fas expression was examined in matched pairs of primary and metastatic cell lines as well as by immunohistochemistry of tissues taken from primary and metastatic sites of spontaneous tumor development. In the sarcoma model, a Fas-resistant/refractory subline was produced in vitro from the parental line by biologic selection against Fas-responsive cells, and it was then compared with the poorly metastatic parental line and to an in vivo-derived subline that was highly metastatic for growth in the lungs. In both tumor models, an inverse correlation was demonstrated between Fas expression and metastatic phenotype. Subsequent studies in the sarcoma model revealed that although the Fas-resistant/refractory subline displayed significant metastatic ability, the parental line from which it was derived exhibited little to no additional metastatic activity if experimentally rendered Fas-resistant by molecular-based strategies or transplanted into a Fas ligand-deficient host. Therefore, these findings suggested that down-regulation of Fas was associated with the metastatic phenotype, but alterations in Fas expression alone were insufficient for acquisition of full metastatic potential. Rather, the ability of such Fas-resistant neoplastic subpopulations to achieve metastatic competence apparently required co-possession of additional malignant characteristics.
IL-1β Scavenging by the Type II IL-1 Decoy Receptor in Human Neutrophils
Authors: Bourke Emer , Cassetti Arianna , Villa Antonello , Fadlon Emma , Colotta Francesco , Mantovani Alberto 
Published: April 2014

AbstractIL-1 elicits its cellular effects by binding a heterodimeric receptor consisting of IL-1RI and the accessory protein, IL-1RAcPr. In addition, it binds to IL-1RII, which lacking signaling function has been ascribed a decoy role. The fate of the ligand following interaction with the decoy receptor was examined in human polymorphonuclear cells (PMN), which express predominantly (&gt;90%) IL-1RII. Incubation of PMN with IL-1β results in a rapid decrease in cell surface-associated ligand accompanied by a concomitant increase in internalized IL-1 with 50–60% of IL-1β located intracellularly within 1 h at 37°C. The use of blocking Abs revealed that IL-1 internalization is mediated exclusively by the decoy receptor. The results of inhibitor analysis demonstrate that internalization requires ATP synthesis and involves clathrin-mediated endocytosis. Following removal of the ligand, the receptor was rapidly re-expressed on the cell surface. Cyclohexamide, a protein synthesis inhibitor, had no effect upon the process, suggesting that the re-expressed receptor was recycled. In addition, human keratinocytes stably transfected with IL-1RII (HaCAT 811) also internalized the IL-1RII with 43% cell surface receptor internalized after 90 min. Immunofluorescence microscopy revealed colocalization of the internalized receptor with wheat germ agglutinin-labeled internalized glycoproteins and early endosome Ag-1, a protein associated with the early endosome compartments, indicative of cellular uptake of IL-1RII by endocytosis. In contrast, little or no internalization was observed in other cells of immune origin. These results suggest that the decoy receptor IL-1RII can act as a scavenger of IL-1, representing a novel autoregulatory mechanism of the IL-1 system.
Mitochondrial Membrane Hyperpolarization Hijacks Activated T Lymphocytes Toward the Apoptotic-Prone Phenotype: Homeostatic Mechanisms of HIV Protease Inhibitors
Authors: Matarrese Paola , Gambardella Lucrezia , Cassone Antonio , Vella Stefano , Cauda Roberto , Malorni Walter 
Published: April 2014

AbstractA decrease of mitochondrial membrane potential has been hypothesized to be a marker of apoptotic cells, including activated T lymphocytes. It was recently demonstrated that HIV protease inhibitors, independently from any viral infection, can hinder lymphocyte apoptosis by influencing mitochondrial homeostasis. To analyze the mechanisms underlying these effects, a specific study was undertaken in both resting and activated human PBL exposed to either receptor (e.g., anti-Fas)- or nonreceptor (e.g., radiation)-mediated apoptotic stimuli. T cell activation was found to be accompanied by a significant increase in mitochondrial membrane potential, or hyperpolarization, which was undetectable in resting cells. We also detected apoptotic hindering by HIV protease inhibitors only in activated T lymphocytes. This was apparently due to the ability of these drugs to block activation-associated mitochondria hyperpolarization, which, in turn, was paralleled by an impairment of cell cycle progression. Remarkably, protease inhibitors also prevented zidovudine-mediated mitochondrial toxicity. Finally, HIV-infected cells from naive patients behaved identically to activated T cells, displaying hyperpolarized mitochondria, while lymphocytes from patients under highly active antiretroviral therapy (which included HIV protease inhibitors) seemed to react as resting cells. Altogether these results clearly indicate that the hyperpolarization state of mitochondria may represent a prerequisite for the sensitization of lymphocytes to the so-called activation-induced cell death. They also suggest that HIV protease inhibitors, by interfering with induction of the mitochondrial hyperpolarization state, can result in cell survival even independent of any viral infection.