bluuebunny/crossref_metadata_2025_split huggingface dataset:
Apolipoprotein E Modulates Clearance of Apoptotic Bodies In Vitro and In Vivo, Resulting in a Systemic Proinflammatory State in Apolipoprotein E-Deficient Mice
Authors: Grainger David J. , Reckless Jill , McKilligin Elaine 
Published: April 2014

Abstract
Apolipoprotein E (apoE) is a 34-kDa glycoprotein involved in lipoprotein transport through interaction with the low-density lipoprotein receptor and related receptors. Recently, it has become clear that apoE binding to its receptors plays a role both in development and in control of the immune system. In this study, we show that apoE modulates the rate of uptake of apoptotic cells by macrophages. In vitro, apoE-deficient macrophages ingest less apoptotic thymocytes (but not latex beads) than wild-type macrophages, and this defect can be corrected by addition of exogenous apoE protein. In vivo, the number of dying macrophages is increased in a range of tissues, including lung and brain. Possibly in response to the larger numbers of persistent apoptotic bodies, the number of live macrophages in these tissues are also increased compared with those of wild-type control mice. In addition to the significant changes in macrophage population dynamics we observed, levels of the proinflammatory cytokine TNF-α and the positive acute phase reactant fibrinogen are also elevated in the livers from apoE-deficient mice. In contrast, neither deletion of the gene encoding the LDL receptor nor cholesterol feeding of wild-type mice affected either the number of apoptotic bodies or the number of live macrophages. We conclude that apoE deficiency results in impaired clearance of apoptotic cell remnants and a functionally relevant systemic proinflammatory condition in mice, independent of its role in lipoprotein metabolism. Any similar reduction of apoE activity in humans may contribute to the pathogenesis of a wide range of chronic diseases including atherosclerosis, dementia, and osteoporosis.
Polymorphisms in the FcεRIβ Promoter Region Affecting Transcription Activity: A Possible Promoter-Dependent Mechanism for Association between FcεRIβ and Atopy
Authors: Nishiyama Chiharu , Akizawa Yushiro , Nishiyama Makoto , Tokura Tomoko , Kawada Hiroshi , Mitsuishi Kouichi , Hasegawa Masanari , Ito Tomonobu , Nakano Nobuhiro , Okamoto Atsushi , Takagi Atsushi , Yagita Hideo , Okumura Ko , Ogawa Hideoki 
Published: April 2014

Abstract
The β subunit of the high-affinity IgE receptor (FcεRI) plays an important role in IgE-mediated allergic reactions as an amplifier for cell surface expression and signal transduction of FcεRI. FcεRIβ is presumed to be one of the genes linked with atopic diseases. However, the validity of the associations previously found between single nucleotide polymorphisms (SNPs) in FcεRIβ and atopic diseases is questionable. In the present study, we found correlation between the SNP of FcεRIβ at +6960A/G, resulting in a Glu237Gly amino acid substitution, and the cell surface expression level of FcεRI on blood basophils, although it has been shown that the Glu237Gly mutation itself does not affect the surface expression or function of FcεRI. We additionally found four SNPs in the promoter region of FcεRIβ, among which −426T/C and −654C/T were tightly linked with +6960A/G. Reporter plasmids carrying the −426C and −654T promoter displayed higher transcriptional activity than those carrying the −426T and −654C promoter. We found that transcription factor YY1 preferentially bound and transactivated the −654T promoter. Furthermore, expression of FcεRI β-chain mRNA in basophils from individuals who have the minor heterozygous genotype was significantly higher than that of the major homozygous genotype. These results suggest that the SNPs in the FcεRIβ promoter are causally linked with atopy via regulation of FcεRI expression.
Immune Responses of Breast Cancer Patients to Mutated Epidermal Growth Factor Receptor (EGF-RvIII, ΔEGF-R, and de2–7 EGF-R)
Authors: Purev Enkhtsetseg , Cai Dewei , Miller Eric , Swoboda Rolf , Mayer Ted , Klein-Szanto Andres , Marincola Francesco M. , Mick Rosemarie , Otvos Laszlo , Wunner William , Birebent Brigitte , Somasundaram Rajasekharan , Wikstrand Carol J. , Bigner Darell , DeMichele Angela , Acs Geza , Berlin Jesse A. , Herlyn Dorothee 
Published: April 2014

AbstractMutated epidermal growth factor receptor (EGF-RvIII, ΔEGF-R, and de2–7 EGF-R) is the result of an 801-bp deletion within the extracellular domain of wild-type EGF-R and is expressed by breast carcinomas, but not by normal breast tissues. EGF-RvIII is expressed both on the surface and in the cytoplasm of tumor cells. Thus, EGF-RvIII is a potential tumor-specific target for both Abs and T cells. However, it is not known whether breast cancer patients can raise immune responses to EGF-RvIII expressed by their tumors. The demonstration of EGF-RvIII-specific immune responses in patients would suggest that immunization of patients with EGF-RvIII vaccines is feasible, because these vaccines may boost a pre-existing immune response. We have evaluated humoral and cellular immune responses to EGF-RvIII in 16 breast cancer patients and three healthy donors. Seven of 16 patients developed EGF-RvIII-specific Abs that bound to isolated EGF-RvIII protein or the protein expressed by EGF-RvIII-transfected mouse fibroblasts. The Abs that bound to EGF-RvIII did not bind to wild-type EGF-R, and anti-EGF-RvIII Abs were not found in the sera of healthy donors. Three patients had EGF-RvIII peptide-specific lymphoproliferative responses, and two of these patients also had humoral immune responses. Humoral and cellular immune responses correlated with EGF-RvIII expression by patients’ tumors in most cases. These studies demonstrate that breast cancer patients specifically recognize EGF-RvIII with an overall immune response rate of 50%, suggesting that patients may benefit from vaccination against EGF-RvIII, boosting pre-existing immune responses.
Constitutive Expression of CCR7 Directs Effector CD8 T Cells into the Splenic White Pulp and Impairs Functional Activity
Authors: Unsoeld Heike , Voehringer David , Krautwald Stefan , Pircher Hanspeter 
Published: April 2014

AbstractAntigenic stimulation down-regulates CCR7 on effector T cells. To analyze the importance of CCR7 down-regulation, transgenic (tg) mice constitutively expressing CCR7 were generated. CD8 T cells with defined Ag specificity were obtained by breeding CCR7-tg mice with P14 TCR-tg mice specific for lymphocytic choriomeningitis virus. Transgenic CCR7 expression did not impair proliferation of P14.CCR7 T cells induced by lymphocytic choriomeningitis virus infection, but prevented CCR7 down-regulation. Compared with wild-type P14 effector cells, P14.CCR7 effector cells, expressing the CCR7 transgene, were increased in the spleen, but decreased in blood and peripheral tissues. Moreover, P14.CCR7 effector cells localized almost exclusively in the splenic white pulp, whereas P14 effector cells were excluded from splenic white pulp cords and were found preferentially in the red pulp. Functional experiments further revealed that P14.CCR7 effector cells were impaired in rapid viral clearance and in inducing Ag-specific delayed-type hypersensitivity reactions. Thus, the present study demonstrates that down-regulation of CCR7 during CD8 T cell activation is important to release effector cells from the white pulp of the spleen, and highlights the importance of effector cell localization in providing rapid immunity.
p21Cip1 and p27Kip1 Act in Synergy to Alter the Sensitivity of Naive T Cells to TGF-β-Mediated G1 Arrest through Modulation of IL-2 Responsiveness
Authors: Wolfraim Lawrence A. , Walz Thomas M. , James Zakiya , Fernandez Tania , Letterio John J. 
Published: April 2014

Abstract
Induction of G1 arrest by TGF-β correlates with the regulation of p21Cip1 and p27Kip1, members of the Cip/Kip family of cyclin-dependent kinase inhibitors (cki). However, no definitive evidence exists that these proteins play a causal role in TGF-β1-induced growth arrest in lymphocytes. In this report we show the suppression of cell cycle progression by TGF-β is diminished in T cells from mice deficient for both p21Cip1 and p27Kip1 (double-knockout (DKO)) only when activated under conditions of optimal costimulation. Although there is an IL-2-dependent enhanced proliferation of CD8+ T cells from DKO mice, TGF-β is able to maximally suppress the proliferation of DKO T cells when activated under conditions of low costimulatory strength. We also show that the induction of p15Ink4b in T cells stimulated in the presence of TGF-β is not essential, as TGF-β also efficiently suppressed proliferation of T cells from p15Ink4b−/− mice. Finally, although these cki are dispensable for the suppression of T cell proliferation by TGF-β, we now describe a Smad3-dependent down-regulation of cdk4, suggesting a potential mechanism underlying to resistance of Smad3−/− T cells to the induction of growth arrest by TGF-β. In summary, the growth suppressive effects of TGF-β in naive T cells are a function of the strength of costimulation, and alterations in the expression of cki modify the sensitivity to TGF-β by lowering thresholds for a maximal mitogenic response.
Environmental and Endogenous Peroxisome Proliferator-Activated Receptor γ Agonists Induce Bone Marrow B Cell Growth Arrest and Apoptosis: Interactions between Mono(2-ethylhexyl)phthalate, 9-cis-Retinoic Acid, and 15-Deoxy-Δ12,14-prostaglandin J2
Authors: Schlezinger Jennifer J. , Howard Gregory J. , Hurst Christopher H. , Emberley Jessica K. , Waxman David J. , Webster Thomas , Sherr David H. 
Published: April 2014

Abstract
The common commercial use of phthalate esters has resulted in significant human exposure to these bioactive compounds. The facts that phthalate ester metabolites, like endogenous PGs, are peroxisome proliferator-activated receptor (PPAR) agonists, and that PPARγ agonists induce lymphocyte apoptosis suggest that phthalate esters are immunosuppressants that could act together with PGs to modulate early B cell development. In this study we examined the effects of a metabolite of one environmental phthalate, mono(2-ethylhexyl)phthalate (MEHP), and 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), on developing B cells. MEHP inhibited [3H]thymidine incorporation by primary murine bone marrow B cells and a nontransformed murine pro/pre-B cell line (BU-11). Cotreatment with a retinoid X receptor α ligand, 9-cis-retinoic acid, decreased [3H]thymidine incorporation synergistically, thereby implicating activation of a PPARγ-retinoid X receptor α complex. These results were similar to those obtained with the natural PPARγ ligand 15d-PGJ2. At moderate MEHP concentrations (25 or 100 μM for primary pro-B cells and a pro/pre-B cell line, respectively), inhibition of [3H]thymidine incorporation resulted primarily from apoptosis induction, whereas at lower concentrations, the inhibition probably reflected growth arrest without apoptosis. Cotreatment of bone marrow B cells with 15d-PGJ2 and MEHP significantly enhanced the inhibition of [3H]thymidine incorporation seen with MEHP alone, potentially mimicking exposure in the bone marrow microenvironment where PG concentrations are high. Finally, MEHP- and 15d-PGJ2-induced death does not result from a decrease in NF-κB activation. These data demonstrate that environmental phthalates can cooperate with an endogenous ligand, 15d-PGJ2, to inhibit proliferation of and induce apoptosis in developing bone marrow B cells, potentially via PPARγ activation.
Folate Deficiency Inhibits the Proliferation of Primary Human CD8+ T Lymphocytes In Vitro
Authors: Courtemanche Chantal , Elson-Schwab Ilan , Mashiyama Susan T. , Kerry Nicole , Ames Bruce N. 
Published: April 2014

Abstract
Folate is required for one-carbon transfer reactions and the formation of purines and pyrimidines for DNA and RNA synthesis. Deficiency of folate can lead to many clinical abnormalities, including macrocytic anemia, cardiovascular diseases, birth defects, and carcinogenesis. The nucleotide imbalance due to folate deficiency causes cell cycle arrest in the S phase and uracil misincorporation into DNA, which may result in DNA double-strand breaks during repair. The role of folate in the immune system has not been fully characterized. We cultured PHA-activated human T lymphocytes in varying concentrations of folate, and measured proliferation, cell cycle, apoptosis, uracil misincorporation, and proportions of Th cells (CD4+) and cytotoxic T (CD8+) cells. Folate deficiency reduced proliferation of T lymphocytes, induced cell cycle arrest in the S phase, induced apoptosis, and increased the level of uracil in DNA. Folate deficiency also increased the CD4+ to CD8+ ratio due to a marked reduction of CD8+ cell proliferation. Folate or nucleoside repletion of folate-deficient cells rapidly restored T lymphocyte proliferation and normal cell cycle, reduced the DNA uracil content, and lowered the CD4+ to CD8+ ratio. These data suggest that folate status may affect the immune system by reducing the capacity of CD8+ cells to proliferate in response to activation.
Single-Stranded DNA Breaks Adjacent to Cytosines Occur during Ig Gene Class Switch Recombination
Authors: Arudchandran Arulvathani , Bernstein Ralph M. , Max Edward E. 
Published: April 2014

AbstractClass switch recombination (CSR) at the DNA level underlies ability of B lymphocytes to switch from expressing IgM to expressing IgG, IgA, or IgE. The mechanism of CSR is largely unknown, but it is clear that CSR is stimulated by T cell signals and is mediated in part by activation-induced deaminase (AID), an enzyme that is also required for somatic hypermutation of Ig genes. In one current model, AID is proposed to initiate CSR by deaminating cytosines in the unpaired nontemplate strand of DNA displaced from its complementary strand by the “sterile” RNA transcript across the switch region. We have used LM-PCR to analyze single-strand breaks in CH12F3-2, a murine cell line that switches in vitro to IgA expression. In contrast to the above model, we have detected CSR-associated ssDNA breaks in the template strand of the H chain α switch region, the strand thought to be complexed with RNA. Most breaks are adjacent to cytosines, consistent with mediation by AID, and occur within the novel consensus sequence C*AG, which occurs much more frequently on the template strand than on the putatively displaced nontemplate strand. These results suggest that AID may target the DNA strand bound to RNA, perhaps resembling APOBEC-3G, a cytosine deaminase related to AID that inhibits HIV replication by mutating viral DNA. Furthermore, the absence of detectable breaks in the nontemplate strand within the DNA segment under study suggests that the two DNA strands are handled differently in the generation or processing of strand breaks.
Arthropod-Derived Histamine-Binding Protein Prevents Murine Allergic Asthma
Authors: Couillin Isabelle , Maillet Isabelle , Vargaftig B. Boris , Jacobs Muazzam , Paesen Guido C. , Nuttall Patricia A. , Lefort Jean , Moser René , Weston-Davies Wynne , Ryffel Bernhard 
Published: April 2014

AbstractBecause histamine receptor type I blockade attenuates allergic asthma, we asked whether complete neutralization of histamine by an arthropod-derived, high affinity histamine-binding protein (EV131) would prevent allergic asthma. Intranasal administration of EV131 given before Ag challenge in immunized mice prevented airway hyperreactivity by 70%, and abrogated peribronchial inflammation, pulmonary eosinophilia, mucus hypersecretion, and IL-4 and IL-5 secretion. Saturation with histamine abrogated the inhibitory effect of EV131 on bronchial hyperreactivity. The inhibitory effect of EV131 on bronchial hyperreactivity was comparable to that of glucocorticosteroids. These results demonstrate that histamine is a critical mediator of allergic asthma. Therefore, complete neutralization of histamine, rather than specific histamine receptor blockade, may have a profound effect on allergic asthma.
Vaccine-Induced Immunity againstHelicobacter pyloriInfection Is Impaired in IL-18-Deficient Mice
Authors: Akhiani Ali A. , Schön Karin , Lycke Nils 
Published: April 2014

AbstractProtective immunity against Helicobacter pylori infection in mice has been associated with a strong Th1 response, involving IL-12 as well as IFN-γ, but recent studies have also demonstrated prominent eosinophilic infiltration, possibly linked to local Th2 activity in the gastric mucosa. In this study we investigated the role of IL-18, because this cytokine has been found to be a coregulator of Th1 development as well as involved in Th2-type responses with local eotaxin production that could influence gastric eosinophilia and resistance to infection. We found that IL-18−/− mice failed to develop protection after oral immunization with H. pylori lysate and cholera toxin adjuvant, indicating an important role of IL-18 in protection. Well-protected C57BL/6 wild-type (WT) mice demonstrated substantial influx of CD4+ T cells and eosinophilic cells in the gastric mucosa, whereas IL-18−/− mice had less gastritis, few CD4+ T cells, and significantly reduced numbers of eosinophilic cells. T cells in well-protected WT mice produced increased levels of IFN-γ and IL-18 to recall Ag. By contrast, unprotected IL-18−/− mice exhibited significantly reduced gastric IFN-γ and specific IgG2a Ab levels. Despite differences in gastric eosinophilic cell infiltration, protected WT and unprotected IL-18−/− mice had comparable levels of local eotaxin, suggesting that IL-18 influences protection via Th1 development and IFN-γ production rather than through promoting local production of eotaxin and eosinophilic cell infiltration.
Shaping Phenotype, Function, and Survival of Dendritic Cells by Cytomegalovirus-Encoded IL-10
Authors: Raftery Martin J. , Wieland Dörte , Gronewald Stefanie , Kraus Annette A. , Giese Thomas , Schönrich Günther 
Published: April 2014

Abstract
Human dendritic cells (DCs) are essential for the antiviral immune response and represent a strategically important target for immune evasion of viruses, including human CMV (HCMV). Recently, HCMV has been discovered to encode a unique IL-10 homologue (cmvIL-10). In this study we investigated the capacity of cmvIL-10 to shape phenotype, function, and survival of DCs. For comparison we included human IL-10 and another IL-10 homologue encoded by EBV, which does not directly target DCs. Interestingly, cmvIL-10 strongly activated STAT3 in immature DCs despite its low sequence identity with human IL-10. For most molecules cmvIL-10 blocked LPS-induced surface up-regulation, confirming its role as an inhibitor of maturation. However, a small number of molecules on LPS-treated DCs including IDO, a proposed tolerogenic molecule, showed a different behavior and were up-regulated in response to cmvIL-10. Intriguingly, the expression of C-type lectin DC-specific ICAM-grabbing nonintegrin, a receptor for HCMV infection found exclusively on DCs, was also enhanced by cmvIL-10. This phenotypic change was mirrored by the efficiency of HCMV infection. Moreover, DCs stimulated with LPS and simultaneously treated with cmvIL-10 retained the function of immature DCs. Finally, cmvIL-10 increased apoptosis associated with DC maturation by blocking up-regulation of the antiapoptotic long form cellular FLIP. Taken together, these findings show potential mechanisms by which cmvIL-10 could assist HCMV to infect DCs and to impair DC function and survival.
Regulation of Found in Inflammatory Zone 1 Expression in Bleomycin-Induced Lung Fibrosis: Role of IL-4/IL-13 and Mediation via STAT-6
Authors: Liu Tianju , Jin Hong , Ullenbruch Matthew , Hu Biao , Hashimoto Naozumi , Moore Bethany , McKenzie Andrew , Lukacs Nicholas W. , Phan Sem H. 
Published: April 2014

Abstract
Found in inflammatory zone (FIZZ)1, also known as resistin-like molecule α, belongs to a novel class of cysteine-rich secreted protein family, named FIZZ/resistin-like molecule, with unique tissue expression patterns. FIZZ1 is induced in alveolar type II epithelial cells (AECs) in bleomycin (BLM)-induced lung fibrosis, and found to induce myofibroblast differentiation in vitro. The objective of this study was to elucidate the regulation of AEC FIZZ1 expression in pulmonary fibrosis. AECs were isolated from rat lungs and the effects of a number of cytokines on FIZZ1 expression were evaluated by RT-PCR. Of all cytokines examined, only IL-4 and IL-13 were effective in stimulating FIZZ1 expression in AECs. Stimulation by IL-4/IL-13 was accompanied by increases in phosphorylated STAT6 and JAK1. FIZZ1 expression was also stimulated by transfection with a STAT6 expression plasmid, but was inhibited by antisense oligonucleotides directed against STAT6. In vivo studies showed that compared with wild-type controls, both IL-4- and IL-13-deficient mice showed reduced BLM-induced lung FIZZ1 expression and fibrosis, which were essentially abolished in IL-4 and IL-13 doubly deficient mice. Furthermore, STAT6-deficient mice showed marked reduction in BLM-induced lung FIZZ1 expression. Thus, IL-4 and IL-13 are potent inducers of AEC FIZZ1 expression via STAT6 and play key roles in BLM-induced lung FIZZ1 expression and fibrosis. This represents a potential mechanism by which IL-4/IL-13 could play a role in the pathogenesis of lung fibrosis.
A Critical Regulatory Role of Leucin Zipper Transcription Factor c-Maf in Th1-Mediated Experimental Colitis
Authors: Weigmann Benno , Nemetz Andrea , Becker Christoph , Schmidt Jan , Strand Dennis , Lehr Hans A. , Galle Peter R. , Ho I.-Cheng , Neurath Markus F. 
Published: April 2014

AbstractIn this study, we investigated the role of c-Maf, a transcription factor known to induce IL-4 production, in inflammatory bowel diseases and experimental colitis. Although Crohn′s disease (CD) is associated with low IL-4 production by T-bet-expressing Th1 cells in the lamina propria, surprisingly a higher expression of c-Maf in these cells was found as compared with control patients. The relevance of this finding was further evaluated in an animal model of CD induced by adoptive transfer of CD4+CD62L+ T cells in RAG-deficient mice. In this Th1-mediated model, an increase of c-Maf-expressing T lymphocytes in the lamina propria over time was observed. Interestingly, adoptive transfer of c-Maf transgenic CD4+CD62L+ T cells in RAG-1-deficient mice resulted in an IL-4-dependent inability to induce colitis and suppressed colitis activity induced by wild-type CD4+CD62L+ T cells. In contrast, transfer of CD4+CD62L− T cells from c-Maf transgenic, but not wild-type mice induced colitis and augmented colitis induced by CD4+CD62L+ T cells from wild-type mice in an IL-4-independent pathway, as determined by macroscopic, histologic, and endoscopic criteria. This was associated with an accumulation of CD4+ T-bet+ CD25+ effector Th1 cells in the lamina propria of colitic mice. Our results reveal a novel regulatory role of c-Maf in colitis. Although overexpression of c-Maf in naive T cells prevents Th1-mediated colitis, overexpression of c-Maf in memory T-bet+ Th1 cells regulates CD25 expression and augments such colitis. Targeting of c-Maf in memory T cells in CD appears to be an attractive target for therapeutic interventions.