bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-1β Regulates Blood-Brain Barrier Permeability via Reactivation of the Hypoxia-Angiogenesis Program
Authors: Argaw Azeb Tadesse , Zhang Yueting , Snyder Brian J. , Zhao Meng-Liang , Kopp Natalya , Lee Sunhee C. , Raine Cedric S. , Brosnan Celia F. , John Gareth R. 
Published: April 2014

AbstractLoss of blood-brain barrier (BBB) integrity is believed to be an early and significant event in lesion pathogenesis in the inflammatory demyelinating disease multiple sclerosis (MS), and understanding mechanisms involved may lead to novel therapeutic avenues for this disorder. Well-differentiated endothelium forms the basis of the BBB, while astrocytes control the balance between barrier stability and permeability via production of factors that restrict or promote vessel plasticity. In this study, we report that the proinflammatory cytokine IL-1β, which is prominently expressed in active MS lesions, causes a shift in the expression of these factors to favor plasticity and permeability. The transcription factor, hypoxia inducible factor-1 (HIF-1), plays a significant role in this switch. Using a microarray-based approach, we found that in human astrocytes, IL-1β induced the expression of genes favoring vessel plasticity, including HIF-1α and its target, vascular endothelial growth factor-A (VEGF-A). Demonstrating relevance to MS, we showed that HIF-1α and VEGF-A were expressed by reactive astrocytes in active MS lesions, while the VEGF receptor VEGFR2/flk-1 localized to endothelium and IL-1 to microglia/macrophages. Suggesting functional significance, we found that expression of IL-1β in the brain induced astrocytic expression of HIF-1α, VEGF-A, and BBB permeability. In addition, we confirmed VEGF-A to be a potent inducer of BBB permeability and angiogenesis, and demonstrated the importance of IL-1β-induced HIF-1α in its regulation. These results suggest that IL-1β contributes to BBB permeability in MS via reactivation of the HIF–VEGF axis. This pathway may represent a potential therapeutic target to restrict lesion formation.
Serum Amyloid A Binding to Formyl Peptide Receptor-Like 1 Induces Synovial Hyperplasia and Angiogenesis
Authors: Lee Mi-Sook , Yoo Seung-Ah , Cho Chul-Soo , Suh Pann-Ghill , Kim Wan-Uk , Ryu Sung Ho 
Published: April 2014

Abstract
Serum amyloid A (SAA) is a major acute-phase reactant, and has been demonstrated to mediate proinflammatory cellular responses. Although SAA has been used as an indicator for a variety of inflammatory diseases, the role of SAA in synovial hyperplasia and proliferation of endothelial cells, a pathological hallmark of rheumatoid arthritis (RA), has yet to be elucidated. In this study, we have demonstrated that SAA promotes the proliferation of human fibroblast-like synoviocytes (FLS). In addition, SAA protects RA FLS against the apoptotic death induced by serum starvation, anti-Fas IgM, and sodium nitroprusside. The activity of SAA appears to be mediated by the formyl peptide receptor-like 1 (FPRL1) receptor, as it was mimicked by the WKYMVm peptide, a specific ligand for FPRL1, but completely abrogated by down-regulating the FPRL1 transcripts with short interfering RNA. The effect of SAA on FLS hyperplasia was shown to be caused by an increase in the levels of intracellular calcium, as well as the activation of ERK and Akt, which resulted in an elevation in the expression of cyclin D1 and Bcl-2. Moreover, SAA stimulated the proliferation, migration, and tube formation of endothelial cells in vitro, and enhanced the sprouting activity of endothelial cells ex vivo and neovascularization in vivo. These observations indicate that the binding of SAA to FPRL1 may contribute to the destruction of bone and cartilage via the promotion of synoviocyte hyperplasia and angiogenesis, thus providing a potential target for the control of RA.
Inhibition of Arginase I Activity by RNA Interference Attenuates IL-13-Induced Airways Hyperresponsiveness
Authors: Yang Ming , Rangasamy Danny , Matthaei Klaus I. , Frew Ailsa J. , Zimmmermann Nives , Mahalingam Suresh , Webb Dianne C. , Tremethick David J. , Thompson Philip J. , Hogan Simon P. , Rothenberg Marc E. , Cowden William B. , Foster Paul S. 
Published: April 2014

AbstractIncreased arginase I activity is associated with allergic disorders such as asthma. How arginase I contributes to and is regulated by allergic inflammatory processes remains unknown. CD4+ Th2 lymphocytes (Th2 cells) and IL-13 are two crucial immune regulators that use STAT6-dependent pathways to induce allergic airways inflammation and enhanced airways responsiveness to spasmogens (airways hyperresponsiveness (AHR)). This pathway is also used to activate arginase I in isolated cells and in hepatic infection with helminths. In the present study, we show that arginase I expression is also regulated in the lung in a STAT6-dependent manner by Th2-induced allergic inflammation or by IL-13 alone. IL-13-induced expression of arginase I correlated directly with increased synthesis of urea and with reduced synthesis of NO. Expression of arginase I, but not eosinophilia or mucus hypersecretion, temporally correlated with the development, persistence, and resolution of IL-13-induced AHR. Pharmacological supplementation with l-arginine or with NO donors amplified or attenuated IL-13-induced AHR, respectively. Moreover, inducing loss of function of arginase I specifically in the lung by using RNA interference abrogated the development of IL-13-induced AHR. These data suggest an important role for metabolism of l-arginine by arginase I in the modulation of IL-13-induced AHR and identify a potential pathway distal to cytokine receptor interactions for the control of IL-13-mediated bronchoconstriction in asthma.
Differential Pattern of Inflammatory Molecule Regulation in Intestinal Epithelial Cells Stimulated with IL-1
Authors: Yan Sen Rong , Joseph Robbie R. , Wang Jun , Stadnyk Andrew W. 
Published: April 2014

AbstractTo better predict the consequences of blocking signal transduction pathways as a means of controlling intestinal inflammation, we are characterizing the pathways up-regulated by IL-1 in intestinal epithelial cells (IEC). IL-1β induced increased mRNA levels of MIP-2, MCP-1, RANTES, inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2) in the IEC-18 cell line. IL-1β activated NF-κB but not ERK or p38. Infecting cells with adenovirus expressing a mutated gene for IκBα (IκBAA) blocked IL-1-induced mRNA increases in MIP-2, MCP-1, and iNOS but not COX-2 or RANTES. Expression of IκBAA attenuated the IL-1-induced increase in COX-2 protein. Unexpectedly, RANTES mRNA increased, and protein was secreted by cells expressing IκBAA in the absence of IL-1. Adenovirus-expressing IκBAA, blocking protein synthesis, and IL-1β all resulted in activation of JNK. The JNK inhibitor SP600125 prevented the RANTES increases by all three stimuli. A human enterocyte line was similarly examined, and both NF-κB and JNK regulate IL-1-induced RANTES secretion. We conclude that in IEC-18, IL-1β-induced increases in mRNA for MIP-2, MCP-1, and iNOS are NF-κB-dependent, whereas regulation of RANTES mRNA is independent of NF-κB but is positively regulated by JNK. IL-1β-induced mRNA increases in COX-2 mRNA are both NF-κB- and MAPK-independent but the translation of COX-2 protein is NF-κB-dependent. This pattern of signaling due to a single stimulus exposed the complexities of regulating inflammatory genes in IEC.
Bacillus Calmette Guerin Vaccination of Human Newborns Induces a Specific, Functional CD8+ T Cell Response
Authors: Murray Rose Ann , Mansoor Nazma , Harbacheuski Ryhor , Soler Jorge , Davids Virginia , Soares Andreia , Hawkridge Anthony , Hussey Gregory D. , Maecker Holden , Kaplan Gilla , Hanekom Willem A. 
Published: April 2014

AbstractMounting evidence points to CD8+ T cells playing an important role in protective immunity against Mycobacterium tuberculosis. The only available vaccine against tuberculosis, bacillus Calmette Guérin (BCG), has traditionally been viewed not to induce these cells optimally. In this study, we show that vaccination of human newborns with BCG does indeed induce a specific CD8+ T cell response. These cells degranulated or secreted IFN-γ, but not both, when infant blood was incubated with BCG. This stimulation also resulted in proliferation and up-regulation of cytotoxic molecules. Overall, the specific CD8+ T cell response was quantitatively smaller than the BCG-induced CD4+ T cell response. Incubation of whole blood with M. tuberculosis also caused CD8+ T cell IFN-γ expression. We conclude that BCG induces a robust CD8+ T cell response, which may contribute to vaccination-induced protection against tuberculosis.
Vector Prime/Protein Boost Vaccine That Overcomes Defects Acquired during Aging and Cancer
Authors: Tang Yucheng , Akbulut Hakan , Maynard Jonathan , Petersen Line , Fang Xiangming , Zhang Wei-Wei , Xia Xiaoqin , Koziol James , Linton Phyllis-Jean , Deisseroth Albert 
Published: April 2014

Abstract
We showed that the Ad-sig-TAA/ecdCD40L vaccine induces a tumor suppressive immune response to the hMUC-1 and rH2N tumor-associated self Ags (TAA) and to the Annexin A1 tumor vascular Ag, even in mice in which anergy exists to these Ags. When the TAA/ecdCD40L protein is given s.c. as a boost following the Ad-sig-TAA/ecdCD40L vector, the levels of the TAA-specific CD8 T cells and Abs increase dramatically over that seen with vector alone, in young (2-mo-old) as well as old (18-mo-old) mice. The Abs induced against hMUC-1 react with human breast cancer. This vaccine also induces a 4-fold decrement of negative regulatory CD4CD25FOXP3-T cells in the tumor tissue of 18-mo-old mice. These results suggest that the Ad-sig-TAA/ecdCD40L vector prime-TAA/ecdCD40L protein boost vaccine platform may be valuable in reducing postsurgery recurrence in a variety of epithelial neoplasms.
Systemic and Local Characterization of Regulatory T Cells in a Chronic Fungal Infection in Humans
Authors: Cavassani Karen A. , Campanelli Ana P. , Moreira Ana P. , Vancim Jaqueline O. , Vitali Lucia H. , Mamede Rui C. , Martinez Roberto , Silva João S. 
Published: April 2014

Abstract
The long-term persistence of pathogens in a host is a hallmark of certain infectious diseases, including schistosomiasis, leishmaniasis, and paracoccidioidomycosis (PCM). Natural regulatory T (Treg) cells are involved in control of the immune responses, including response to pathogens. Because CTLA-4 is constitutively expressed in Treg cells and it acts as a negative regulator of T cell activation in patients with PCM, here we investigated the involvement of Treg cells in the control of systemic and local immune response in patients with PCM. We found that the leukocyte subsets were similar in patients and controls, except for CD11c+CD1a+ cells. However, a higher frequency of CD4+CD25+ T cells expressing CTLA-4, glucorticoid-inducible TNFR, membrane-bound TGF-β, and forkhead-box 3 were observed in PBMC of patients. In accordance, these cells exhibited stronger suppressive activity when compared with those from controls (94.0 vs 67.5% of inhibition of allogeneic T cell proliferation). In addition, the data showed that CD4+CD25+ T cells expressing CTLA-4+, glucocorticoid-inducible TNFR positive, CD103+, CD45RO+, membrane-bound TGF-β, forkhead-box 3 positive, and the chemokines receptors CCR4 and CCR5 accumulate in the Paracoccidioides brasiliensis-induced lesions. Indeed, the secreted CCL17 and CCL22, both associated with the migration of Treg cells to peripheral tissues, were also detected in the biopsies. Moreover, the CD4+CD25+ T cell derived from lesions, most of them TGF-β+, also exhibited functional activity in vitro. Altogether, these data provide the first evidence that Treg cells play a role in controlling local and systemic immune response in patients with a fungal-induced granulomatous disease advancing our understanding about the immune regulation in human chronic diseases.
Impairment of Dendritic Cell Functionality and Steady-State Number in Obese Mice
Authors: Macia Laurence , Delacre Myriam , Abboud Georges , Ouk Tan-Sothéa , Delanoye Anne , Verwaerde Claudie , Saule Pasquine , Wolowczuk Isabelle 
Published: April 2014

AbstractThere is a finely tuned interplay between immune and neuroendocrine systems. Metabolic disturbances like obesity will have serious consequences on immunity both at the cellular and at the cytokine expression levels. Our in vivo results confirm the immune deficiency of ob/ob mice, leptin deficient and massively obese, characterized by a reduced Ag-specific T cell proliferation after keyhole limpet hemocyanin immunization. In this report, we show that dendritic cells (DCs), major APCs involved in T lymphocyte priming, are affected in obese mice. Both their function and their steady-state number are disturbed. We demonstrate that DCs from ob/ob mice are less potent in stimulation of allogenic T cells in vitro. This impaired functionality is not associated with altered expression of phenotypic markers but with the secretion of immunosuppressive cytokines such as TGF-β. Moreover, we show increased in vivo steady-state number of epidermal DCs in ob/ob mice, which is not due to a migratory defect. The ob/ob mice are characterized by the absence of functional leptin, a key adipokine linking nutrition, metabolism, and immune functions. Interestingly, intradermal injection of leptin is able to restore epidermal DC number in obese mice. Thus, DCs might be directly sensitive to metabolic disturbances, providing a partial explanation of the immunodeficiency associated with obesity.
TCRγ Silencing during αβ T Cell Development Depends upon Pre-TCR-Induced Proliferation
Authors: Ferrero Isabel , Mancini Stéphane J. C. , Grosjean Frederic , Wilson Anne , Otten Luc , MacDonald H. Robson 
Published: April 2014

AbstractDuring thymus development, immature T cells become committed to two distinct lineages based upon expression of αβ or γδ TCR. In the αβ lineage, developing thymocytes progressively extinguish transcription of the TCRγ genes by a poorly understood process known as γ silencing. We show that αβ lineage thymocytes in mice lacking a functional pre-TCR undergo limited proliferation and fail to silence TCRγ genes during development. Stimulation of pre-TCR-deficient immature thymocytes with anti-CD3 Abs does not directly down-regulate TCRγ transcription but restores TCRγ silencing following proliferation. Collectively our data reveal an important role for pre-TCR induced proliferation in activating the TCRγ silencer in αβ lineage thymocytes, a process that may reinforce αβ or γδ lineage commitment.
Endogenous IL-1R1 Signaling Is Critical for Cognate CD4+ T Cell Help for Induction of In Vivo Type 1 and Type 2 Antipolysaccharide and Antiprotein Ig Isotype Responses to IntactStreptococcus pneumoniae, but Not to a Soluble Pneumococcal Conjugate Vaccine
Authors: Chen Quanyi , Sen Goutam , Snapper Clifford M. 
Published: April 2014

AbstractMyD88−/− mice exhibit defective innate, diminished CD4+ T cell-dependent (TD) type 1, but enhanced type 2, humoral immunity in response to intact Streptococcus pneumoniae (Pn). Because type 1 IL-1R (IL-1R1) signaling is MyD88 dependent, a role for endogenous IL-1 was determined. IL-1R1−/−, in contrast to MyD88−/−, mice exhibited relatively intact innate splenic cytokine expression in response to Pn. Nevertheless, IL-1R1−/−, like MyD88−/−, mice were more sensitive to killing with live Pn relative to wild-type controls. Although IL-1R1−/− mice elicited a normal T cell-independent IgM antipolysaccharide (PS) response to heat-killed Pn, the induction of PS- and protein-specific cognate, but not noncognate, TD type 1 and type 2 IgG isotypes were markedly reduced. Additionally, CD4+ T cells from Pn-primed IL-1R1−/− mice failed to elicit IFN-γ, IL-5, or IL-13 secretion upon restimulation with Pn in vitro, whereas MyD88−/− mice secreted normal levels of IFN-γ and enhanced levels of IL-5 and IL-13. In contrast, IgG responses to a soluble, pneumococcal protein-PS conjugate, with or without adjuvant, showed little dependence on IL-1R1 and normal CD4+ T cell priming. These data are the first to demonstrate a nonredundant role for endogenous IL-1 in TD induction of humoral immune responses to an intact pathogen, although not a pathogen-derived soluble conjugate, suggesting that antigenic context is a key determinant for IL-1 dependence. These data further suggest that IL-1 may be critical for preserving CD4+ Th2 function in the presence, but not absence, of MyD88-dependent signaling via TLRs.
Age and Vitamin E-Induced Changes in Gene Expression Profiles of T Cells
Authors: Han Sung Nim , Adolfsson Oskar , Lee Cheol-Koo , Prolla Tomas A. , Ordovas Jose , Meydani Simin Nikbin 
Published: April 2014

AbstractT cells are vulnerable to age-associated changes. Vitamin E has been shown to improve T cell functions in the old. We studied gene expression profiles of T cells to better understand the underlying mechanisms of age and vitamin E-induced changes in T cell function. Young and old C57BL mice were fed diets containing 30 (control) or 500 (supplemented) ppm of vitamin E for 4 wks. Gene expression profiles of T cells were assessed using microarray analysis with/without anti-CD3/anti-CD28 stimulation. Genes associated with cytokines/chemokines, transcriptional regulation, signal transduction, cell cycle, and apoptosis were significantly up-regulated upon stimulation. Higher SOCS3 and lower growth factor independent 1 (Gfi-1) expression in old T cells may contribute to age-associated decline in proliferation. Higher Gadd45 and lower Bcl2 expression may contribute to increased apoptosis in old T cells. Vitamin E supplementation resulted in higher expression of genes involved in cell cycle regulation (Ccnb2, Cdc2, Cdc6) in old T cells. Vitamin E supplementation resulted in higher up-regulation of IL-2 expression in young and old T cells and lower up-regulation of IL-4 expression in old T cells following stimulation. These findings suggest that aging has significant effects on the expression of genes associated with signal transduction, transcriptional regulation, and apoptosis pathways in T cells, and vitamin E has a significant impact on the expression of genes associated with cell cycle and Th1/Th2 balance in old T cells. Further studies are needed to determine whether these changes are due to the effects of aging at a single-cell level or to the shift in the ratio of naïve:memory T cells with age.
Incomplete Differentiation of Antigen-Specific CD8 T Cells in Tumor-Draining Lymph Nodes
Authors: Hargadon Kristian M. , Brinkman C. Colin , Sheasley-O’Neill Stacey L. , Nichols Lisa A. , Bullock Timothy N. J. , Engelhard Victor H. 
Published: April 2014

AbstractCD8 T cells lacking effector activity have been recovered from lymphoid organs of mice and patients with progressing tumors. We explored the basis for lack of effector activity in tumor-bearing mice by evaluating Ag presentation and CD8 T cell function in lymphoid organs over the course of tumor outgrowth. Early after tumor injection, cross-presentation by bone marrow-derived APC was necessary for T cell activation, inducing proliferation and differentiation into IFN-γ-producing, cytolytic effectors. At later stages of outgrowth, tumor metastasized to draining lymph nodes. Both cross- and direct presentation occurred, but T cell differentiation induced by either modality was incomplete (proliferation without cytokine production). T cells within tumor-infiltrated nodes differentiated appropriately if Ag was presented by activated, exogenous dendritic cells. Thus, activated T cells lacking effector function develop through incomplete differentiation in the lymph nodes of late-stage tumor-bearing mice, rather than through suppression of previously differentiated cells.
Bap31 Enhances the Endoplasmic Reticulum Export and Quality Control of Human Class I MHC Molecules
Authors: Ladasky John J. , Boyle Sarah , Seth Malini , Li Hewang , Pentcheva Tsvetelina , Abe Fumiyoshi , Steinberg Steven J. , Edidin Michael 
Published: April 2014

AbstractThe assembly of class I MHC molecules and their export from the endoplasmic reticulum (ER) is governed by chaperones and accessory proteins. We present evidence that the putative cargo receptor protein Bap31 participates in the transport and the quality control of human class I molecules. Transfection of the human adenocarcinoma cell line HeLa with yellow fluorescent protein-Bap31 chimeras increased surface levels of class I in a dose-dependent manner, by as much as 3.7-fold. The increase in surface class I resulted from an increase in the rate of export of newly synthesized class I molecules to the cell surface and from an increase in the stability of the exported molecules. We propose that Bap31 performs quality control on class I molecules in two distinct phases: first, by exporting peptide-loaded class I molecules to the ER/Golgi intermediate compartment, and second, by retrieving class I molecules that have lost peptides in the acidic post-ER environment. This function of Bap31 is conditional or redundant, because we find that Bap31 deficiency does not reduce surface class I levels. Overexpression of the Bap31 homolog, Bap29, decreases surface class levels in HeLa, indicating that it does not substitute for Bap31.
5-Hydroxytryptamine Induces Mast Cell Adhesion and Migration
Authors: Kushnir-Sukhov Nataliya M. , Gilfillan Alasdair M. , Coleman John W. , Brown Jared M. , Bruening Sandra , Toth Miklos , Metcalfe Dean D. 
Published: April 2014

AbstractThe neurotransmitter serotonin (5-hydroxytryptamine (5-HT)) is implicated in enhancing inflammatory reactions of skin, lung, and gastrointestinal tract. To determine whether 5-HT acts, in part, through mast cells (MC), we first established that mouse bone marrow-derived MC (mBMMC) and human CD34+-derived MC (huMC) expressed mRNA for multiple 5-HT receptors. We next determined the effect of 5-HT on mouse and human MC degranulation, adhesion, and chemotaxis. We found no evidence that 5-HT degranulates MC or modulates IgE-dependent activation. 5-HT did induce mBMMC and huMC adherence to fibronectin; and immature and mature mBMMC and huMC migration. Chemotaxis was accompanied by actin polymerization. Using receptor antagonists and pertussis toxin, we identified 5-HT1A as the principal receptor mediating the effects of 5-HT on MC. mBMMC from the 5-HT1A receptor knockout mouse (5-HT1AR−/−) did not respond to 5-HT. 5-HT did induce accumulation of MC in the dermis of 5-HT1AR+/+ mice, but not in 5-HT1AR−/− mice. These studies are the first to demonstrate an effect of 5-HT on MC. Furthermore, both mouse and human MC respond to 5-HT through the 5-HT1A receptor. Our data are consistent with the conclusion that 5-HT promotes inflammation by increasing MC at the site of tissue injury.