bluuebunny/crossref_metadata_2025_split huggingface dataset:
Critical Roles for Both STAT1-Dependent and STAT1-Independent Pathways in the Control of Primary Dengue Virus Infection in Mice
Authors: Shresta Sujan , Sharar Kristin L. , Prigozhin Daniil M. , Snider Heidi M. , Beatty P. Robert , Harris Eva 
Published: April 2014

Abstract
Dengue virus (DEN), a flavivirus, causes dengue fever and dengue hemorrhagic fever/dengue shock syndrome, the most common mosquito-borne viral illnesses in humans worldwide. In this study, using STAT1−/− mice bearing two different mutant stat1 alleles in the 129/Sv/Ev background, we demonstrate that IFNR-dependent control of primary DEN infection involves both STAT1-dependent and STAT1-independent mechanisms. The STAT1 pathway is necessary for clearing the initial viral load, whereas the STAT1-independent pathway controls later viral burden and prevents DEN disease in mice. The STAT1-independent responses in mice with primary DEN infection included the early activation of B and NK cells as well as the up-regulation of MHC class I molecules on macrophages and dendritic cells. Infection of bone marrow-derived dendritic cell cultures with either DEN or Sindbis virus, another positive-strand RNA virus, confirmed the early vs late natures of the STAT1-dependent and STAT1-independent pathways. Collectively, these data begin to define the nature of the STAT1-dependent vs the STAT1-independent pathway in vivo.
Interferon-γ Inhibits T84 Epithelial Cell Migration by Redirecting Transcytosis of β1 Integrin from the Migrating Leading Edge
Authors: Tong Qiao , Vassilieva Elena V. , Ivanov Andrei I. , Wang Zili , Brown Gregory T. , Parkos Charles A. , Nusrat Asma 
Published: April 2014

Abstract
Intestinal inflammation is associated with epithelial damage and formation of mucosal wounds. Epithelial cells migration is required for wound closure. In inflammatory status, migrating epithelial cells are exposed to proinflammatory cytokines such as IFN-γ. However, influence of such cytokines on intestinal epithelial wound closure remains unknown. The present study was designed to investigate the effect of IFN-γ on migration of model T84 intestinal epithelial cells and recovery of epithelial wounds. IFN-γ significantly inhibited rate of T84 cell migration and closure of epithelial wounds. This effect was accompanied by the formation of large aberrant lamellipodia at the leading edge as well as significant decrease in the number of β1 integrin containing focal adhesions. IFN-γ exposure increased endocytosis of β1 integrin and shifted its accumulation from early/recycling endosomes at the leading edge to a yet unidentified compartment at the cell base. This redirection in β1 integrin transcytosis was inhibited by depolymerization of microtubules with nocodazole and was unaffected by stabilization of microtubules with docetaxel. These results suggest that IFN-γ attenuates epithelial wound closure by microtubule-dependent redirection of β1 integrin transcytosis from the leading edge of migrating cells thereby inhibiting adequate turnover of focal adhesion complexes and cell migration.
Transcriptional Induction of Matrix Metalloproteinase-9 in the Chondrocyte and Synoviocyte Cells Is Regulated via a Novel Mechanism: Evidence for Functional Cooperation between Serum Amyloid A-Activating Factor-1 and AP-1
Authors: Ray Alpana , Bal B. Sonny , Ray Bimal K. 
Published: April 2014

Abstract
Increased expression of matrix metalloproteinase-9 (MMP-9) by IL-1β and TNF-α is regarded as a key factor in the degradation of cartilage during arthritis. However, the underlying molecular mechanism of this induction process especially in the cells of the joint capsule remains elusive. Chondrocytes and synoviocytes, the resident cells of joint capsule, markedly increase transcription of MMP-9 in response to IL-1β- and TNF-α-mediated stimulation. Using progressively deleted and mutant promoter constructs of MMP-9, we show that serum amyloid A-activating factor (SAF)-1, a novel transcription factor, and the AP-1 family of proteins cooperatively regulate cytokine-mediated induction of MMP-9 in the resident cells of the joint capsule. In the MMP-9 promoter, SAF-1 and AP-1 DNA-binding elements are present in close proximity with only 14 nucleotides apart. SAF-1 DNA-binding activity is increased in both cytokine-stimulated cells as well as in osteoarthritic cartilage tissues. Although overexpression of SAF-1 could increase expression of the MMP-9 promoter and endogenous MMP-9 gelatinolytic activity, for maximal induction of MMP-9 gene concurrent participation of SAF-1 and AP-1 is required. Mutation of either one of these two elements resulted in a severe reduction in cytokine responsiveness of MMP-9 promoter and compromised the transactivation potential of both SAF-1 and AP-1. Simultaneous requirement for two distinct DNA-binding elements suggests that SAF-1 and AP-1 function in a mutually beneficial manner acting as essential coactivators to drive cytokine-mediated transcriptional activation of MMP-9.
Regulation of Lipopolysaccharide-Induced Lung Inflammation by Plasminogen Activator Inhibitor-1 through a JNK-Mediated Pathway
Authors: Arndt Patrick G. , Young Scott K. , Worthen G. Scott 
Published: April 2014

AbstractThe neutrophil is of undoubted importance in lung inflammation after exposure to LPS. We have shown recently that systemic inhibition of JNK decreased neutrophil recruitment to the lung after exposure to LPS, although the mechanisms underlying this inhibition are incompletely understood. As plasminogen activator inhibitor-1 (PAI-1) accentuates cell migration, with JNK activation recently shown to up-regulate PAI-1 expression, this suggested that systemic JNK inhibition may down-regulate LPS-induced pulmonary neutrophil recruitment through a decrease in PAI-1 expression. We show in this study that exposure of mice to aerosolized LPS increased PAI-1 expression in the lung and alveolar compartment, which was decreased by pretreatment with the JNK inhibitor SP600125. Exogenous, intratracheally administered PAI-1 prevented the inhibition of pulmonary neutrophil recruitment in the setting of systemic JNK inhibition, thereby suggesting a role for PAI-1 in the JNK-mediated pathway regulating LPS-induced neutrophil recruitment. In addition, PAI-1−/− mice had a decrease in neutrophil recruitment to the alveolar compartment after exposure to LPS, compared with wild-type controls, further suggesting a role for PAI-1 in LPS-induced lung inflammation. An increase in the intravascular level of KC is a likely mechanism for the inhibition of pulmonary neutrophil recruitment after LPS exposure in the setting of decreased PAI-1 expression, as systemic KC levels after exposure to LPS were increased in PAI-1-deficient mice and in mice pretreated with SP600125, with augmentation of intravascular KC levels inhibiting neutrophil recruitment to the lung after exposure to LPS.
The Urokinase/Urokinase Receptor System Mediates the IgG Immune Complex-Induced Inflammation in Lung
Authors: Shushakova Nelli , Eden Gabriele , Dangers Marc , Zwirner Joerg , Menne Jan , Gueler Faikah , Luft Friedrich C. , Haller Hermann , Dumler Inna 
Published: April 2014

Abstract
Immune complex (IC) deposition induces an acute inflammatory response with tissue injury. IC-induced inflammation is mediated by inflammatory cell infiltration, a process highly regulated by the cell surface-specific receptor (uPAR), a binding partner for the urokinase-type plasminogen activator (uPA). We assessed the role of the uPA/uPAR system in IC-induced inflammation using the pulmonary reverse passive Arthus reaction in mice lacking uPA and uPAR compared with their corresponding wild-type controls. Both uPA-deficient C57BL/6J (uPA−/−) and uPAR-deficient mice on a mixed C57BL/6J (75%) × 129 (25%) background (uPAR−/−) demonstrated a marked reduction of the inflammatory response due to decreased production of proinflammatory mediators TNF-α and Glu-Leu-Arg (ELR)-CXC chemokine MIP-2. In uPAR−/− animals, the reduction of inflammatory response was more pronounced because of decreased migratory capacity of polymorphonuclear leukocytes. We show that the uPA/uPAR system is activated in lung of wild-type mice, particularly in resident alveolar macrophages (AM), early in IC-induced alveolitis. This activation is necessary for an adequate C5a anaphylatoxin receptor signaling on AM that, in turn, modulates the functional balance of the activating/inhibitory IgG FcγRs responsible for proinflammatory mediator release. These data provide the first evidence that the uPA/uPAR plays an important immunoregulatory role in the initiation of the reverse passive Arthus reaction in the lung by setting the threshold for C5a anaphylatoxin receptor/FcγR activation on AM. The findings indicate an important link between the uPA/uPAR system and the two main components involved in the IC inflammation, namely, complement and FcγRs.
Uterine NK Cells Mediate Inflammation-Induced Fetal Demise in IL-10-Null Mice
Authors: Murphy Shaun P. , Fast Loren D. , Hanna Nazeeh N. , Sharma Surendra 
Published: April 2014

Abstract
Specialized NK cells are recruited in high numbers to the mammalian embryo implantation sites, yet remain pregnancy compatible. It is not well understood whether uterine NK (uNK) cells become adversely activated and mediate fetal demise, a common complication of early pregnancy. In this study we show that mating of IL-10−/− mice resulted in fetal resorption or intrauterine growth restriction in response to very low doses of LPS. Pregnancy in congenic wild-type mice was normal even at 10-fold higher LPS doses. Fetal resorption in IL-10−/− mice was associated with a significant increase in uNK cell cytotoxic activation and invasion into the placenta. Depletion of uNK cells, TNF-α neutralization, or IL-10 administration rescued pregnancy in LPS-treated IL-10−/− animals. Our results identify an immune mechanism of fetal demise involving IL-10 deficiency, NK cells, and inflammation. These results may provide insight into adverse pregnancy outcomes in humans.
Mast Cell Survival and Activation by IgE in the Absence of Antigen: A Consideration of the Biologic Mechanisms and Relevance
Authors: Kawakami Toshiaki , Kitaura Jiro 
Published: April 2014

AbstractMast cells are not only major effector cells in allergy and host defense against parasites and bacteria but also important cellular components in other immune responses. Recent studies on the effects of monomeric IgE on mast cell survival and activation have made an impact on our view of the IgE binding to its high-affinity receptors, FcεRI. Traditionally, IgE binding to FcεRI has been considered as a passive action of “sensitization” before receptor aggregation by Ag. However, recent studies indicate that at high concentrations some monoclonal IgEs have effects on mast cells similar to or identical to those induced by IgE+Ag stimulation. These effects may be due to induction of FcεRI aggregation by these IgEs in the absence of Ag. This review will synthesize recent findings of the heterogeneity of IgEs in their ability to induce survival and activation events, their mechanisms, the potential in vivo significance of IgE-FcεRI interactions, and the implications of the mouse studies to human diseases.
Cutting Edge: Bacterial Modulation of Epithelial Signaling via Changes in Neddylation of Cullin-1
Authors: Collier-Hyams Lauren S. , Sloane Valerie , Batten Brigid C. , Neish Andrew S. 
Published: April 2014

Abstract
The human enteric flora plays a significant role in intestinal health and disease. Certain enteric bacteria can inhibit the NF-κB pathway by blockade of IκB-α ubiquitination. IκB-α ubiquitination is catalyzed by the E3-SCFβTrCP ubiquitin ligase, which is itself regulated via covalent modification of the cullin-1 subunit by the ubiquitin-like protein NEDD8. Neddylation is a biochemical event associated with diverse cellular processes related to cell signaling, however, physiological regulation of cullin neddylation has not been described in mammalian systems. We report that interaction of nonpathogenic bacteria with epithelial cells resulted in a rapid loss of neddylated Cul-1 and consequent repression of the NF-κB pathway. This observation may explain the ability of intestinal bacterial communities to influence diverse eukaryotic processes in general and inflammatory tolerance of the mammalian intestinal epithelia specifically.
Regulated Costimulation in the Thymus Is Critical for T Cell Development: Dysregulated CD28 Costimulation Can Bypass the Pre-TCR Checkpoint
Authors: Williams Joy A. , Hathcock Karen S. , Klug David , Harada Yohsuke , Choudhury Baishakhi , Allison James P. , Abe Ryo , Hodes Richard J. 
Published: April 2014

AbstractExpression of CD28 is highly regulated during thymic development, with CD28 levels extremely low on immature thymocytes but increasing dramatically as CD4−CD8− cells initiate expression of TCRβ. B7-1 and B7-2, the ligands for CD28, have a restricted distribution in the thymic cortex where immature thymocytes reside and are more highly expressed in the medulla where the most mature thymocytes are located. To determine the importance of this regulated CD28/B7 expression for T cell development, we examined the effect of induced CD28 signaling of immature thymocytes in CD28/B7-2 double-transgenic mice. Strikingly, we found that differentiation to the CD4+CD8+ stage in CD28/B7-2 transgenics proceeds independent of the requirement for TCRβ expression manifest in wild-type thymocytes, occurring even in Rag− or CD3ε− knockouts. These findings indicate that signaling of immature thymocytes through CD28 in the absence of TCR- or pre-TCR-derived signals can promote an aberrant pathway of T cell differentiation and highlight the importance of finely regulated physiologic expression of CD28 and B7 in maintaining integrity of the “β” checkpoint for pre-TCR/TCR-dependent thymic differentiation.
The Mannich Base NC1153 Promotes Long-Term Allograft Survival and Spares the Recipient from Multiple Toxicities
Authors: Stepkowski Stanislaw M. , Kao Judy , Wang Mou-Er , Tejpal Neelam , Podder Hemangshu , Furian Lucrezia , Dimmock Jonathan , Jha Amitabh , Das Umashankar , Kahan Barry D. , Kirken Robert A. 
Published: April 2014

AbstractJAK3 is a cytoplasmic tyrosine kinase with limited tissue expression but is readily found in activated T cells. Patients lacking JAK3 are immune compromised, suggesting that JAK3 represents a therapeutic target for immunosuppression. Herein, we show that a Mannich base, NC1153, blocked IL-2-induced activation of JAK3 and its downstream substrates STAT5a/b more effectively than activation of the closely related prolactin-induced JAK2 or TNF-α-driven NF-κB. In addition, NC1153 failed to inhibit several other enzymes, including growth factor receptor tyrosine kinases, Src family members, and serine/threonine protein kinases. Although NC1153 inhibited proliferation of normal human T cells challenged with IL-2, IL-4, or IL-7, it did not block T cells void of JAK3. In vivo, a 14-day oral therapy with NC1153 significantly extended survival of MHC/non-MHC mismatched rat kidney allografts, whereas a 90-day therapy induced transplantation tolerance (&gt;200 days). Although NC1153 acted synergistically with cyclosporin A (CsA) to prolong allograft survival, it was not nephrotoxic, myelotoxic, or lipotoxic and did not increase CsA-induced nephrotoxicity. In contrast to CsA, NC1153 was not metabolized by cytochrome P450 3A4. Thus, NC1153 prolongs allograft survival without several toxic effects associated with current immunosuppressive drugs.
Virus-Induced Inhibition of CD1d1-Mediated Antigen Presentation: Reciprocal Regulation by p38 and ERK
Authors: Renukaradhya Gourapura J. , Webb Tonya J. Roberts , Khan Masood A. , Lin Yin Ling , Du Wenjun , Gervay-Hague Jacquelyn , Brutkiewicz Randy R. 
Published: April 2014

AbstractA critical component of the host’s innate immune response involves lipid Ag presentation by CD1d molecules to NK T cells. In this study we used murine CD1d1-transfected L (L-CD1) cells to study the effect of viruses on CD1d-mediated Ag presentation to NKT cells and found that an infection with vesicular stomatitis and vaccinia (but not lymphocytic choriomeningitis) virus inhibited murine CD1d1-mediated Ag presentation. This was under the reciprocal control of the MAPKs, p38 and ERK, and was due to changes in the intracellular trafficking of CD1d1. The reciprocal regulation of CD1d1-mediated Ag presentation by MAPK suggests that the targeting of these pathways is a novel means of immune evasion by viruses.
An Organized Medullary Epithelial Structure in the Normal Thymus Expresses Molecules of Respiratory Epithelium and Resembles the Epithelial Thymic Rudiment of Nude Mice
Authors: Dooley James , Erickson Matt , Farr Andrew G. 
Published: April 2014

Abstract
The expression of tissue-specific Ags (TSA) within the thymic environment has emerged as an important contribution to the establishment of self-tolerance. The mechanistic basis for this property is poorly understood. One model has proposed stochastic derepression of gene expression by mature medullary epithelial cells, whereas another model has suggested that this property of thymic epithelial cells reflects transcriptional activity during their differentiation. Most of the analyses of thymic TSA expression have been done with populations of dissociated thymic epithelial cells; therefore, there is little information regarding the spatial pattern of TSA expression within the thymus. We have evaluated a subset of thymic epithelial cells in the murine thymus that display several unique features. First, within the normal thymus, they form cysts that express several TSA of respiratory epithelium and exhibit some morphological features consistent with respiratory epithelium. These cells also display a phenotypic profile that has been proposed for immature thymic epithelium. The cystic epithelia in the normal thymus and in the nude thymic rudiment are phenotypically very similar, suggesting that they may have a similar developmental program. The coordinated expression of respiratory TSA by an organized subset of thymic epithelial cells and the phenotypic resemblance of these cells to progenitor cells seem consistent with a developmental basis for TSA expression by thymic epithelial cells. Finally, epitopes that define thymic epithelial heterogeneity are reciprocally expressed by respiratory epithelium, which raises interesting questions regarding the developmental relationship of different endodermal derivatives.
αEβ7 (CD103) Expression Identifies a Highly Active, Tonsil-Resident Effector-Memory CTL Population
Authors: Woodberry Tonia , Suscovich Todd J. , Henry Leah M. , August Meredith , Waring Michael T. , Kaur Amitinder , Hess Christoph , Kutok Jeffery L. , Aster Jon C. , Wang Frederick , Scadden David T. , Brander Christian 
Published: April 2014

AbstractThe characterization of antiviral CTL responses has largely been limited to assessing Ag-specific immune responses in the peripheral blood. Consequently, there is an incomplete understanding of the cellular immune responses at mucosal sites where many viruses enter and initially replicate and how the Ag specificity and activation status of CTL derived from these mucosal sites may differ from that of blood-derived CTL. In this study, we show that EBV-specific CTL responses in the tonsils are of comparable specificity and breadth but of a significantly higher magnitude compared with responses in the peripheral blood. EBV-specific, tonsil-resident, but not PBMC-derived, T cells expressed the integrin/activation marker CD103 (αEβ7), consistent with the detection of its ligand, E-cadherin, on tonsillar squamous cells. These CD8-positive, CD103-positive, tonsil-derived CTL were largely CCR7- and CD45RA- negative effector-memory cells and responded to lower Ag concentrations in in vitro assays than their CD103-negative PBMC-derived counterparts. Thus, EBV-specific CTL in the tonsil, a crucial site for EBV entry and replication, are of greater magnitude and phenotypically distinct from CTL in the peripheral blood and may be important for effective control of this orally transmitted virus.
Stepwise Development of Committed Progenitors in the Bone Marrow That Generate Functional T Cells in the Absence of the Thymus
Authors: García-Ojeda Marcos E. , Dejbakhsh-Jones Sussan , Chatterjea-Matthes Devavani , Mukhopadhyay Aditi , BitMansour Andrew , Weissman Irving L. , Brown Janice M. Y. , Strober Samuel 
Published: April 2014

AbstractWe identified committed T cell progenitors (CTPs) in the mouse bone marrow that have not rearranged the TCRβ gene; express a variety of genes associated with commitment to the T cell lineage, including GATA-3, T cell-specific factor-1, Cβ, and Id2; and show a surface marker pattern (CD44+CD25−CD24+CD5−) that is similar to the earliest T cell progenitors in the thymus. More mature committed intermediate progenitors in the marrow have rearranged the TCR gene loci, express Vα and Vβ genes as well as CD3ε, but do not express surface TCR or CD3 receptors. CTPs, but not progenitors from the thymus, reconstituted the αβ T cells in the lymphoid tissues of athymic nu/nu mice. These reconstituted T cells vigorously secreted IFN-γ after stimulation in vitro, and protected the mice against lethal infection with murine CMV. In conclusion, CTPs in wild-type bone marrow can generate functional T cells via an extrathymic pathway in athymic nu/nu mice.
Gs Protein-Coupled Adenosine Receptor Signaling and Lytic Function of Activated NK Cells
Authors: Raskovalova Tatiana , Huang Xiaojun , Sitkovsky Michail , Zacharia Lefteris C. , Jackson Edwin K. , Gorelik Elieser 
Published: April 2014

AbstractThe effect of adenosine and its analogues on the cytotoxic activity of IL-2-activated NK cells was investigated. Adenosine is an endogenous ligand for four different adenosine receptor (AdoR) subtypes (AdoRA1, AdoRA2A, AdoRA2B, and AdoRA3). Increased concentrations of adenosine were found in ascites of MethA sarcoma or in culture medium of 3LL Lewis lung carcinoma growing under hypoxic conditions. We hypothesize that intratumor adenosine impairs the ability of lymphokine-activated killer (LAK) cells to kill tumor cells. The effect of AdoR engagement on LAK cells cytotoxic activity was analyzed using AdoR agonists and antagonists as well as LAK cells generated from AdoR knockout mice. Adenosine and its analogues efficiently inhibited the cytotoxic activity of LAK cells. CGS21680 (AdoRA2A agonist) and 5-N-ethylcarboxamide adenosine (NECA) (AdoRA2A/ADoRA2B agonist) inhibited LAK cell cytotoxicity in parallel with their ability to increase cAMP production. The inhibitory effects of stable adenosine analog 2-chloroadenosine (CADO) and AdoRA2 agonists were blocked by AdoRA2 antagonist ZM 241385. Adenosine and its analogues impair LAK cell function by interfering with both perforin-mediated and Fas ligand-mediated killing pathways. Studies with LAK cells generated from AdoRA1−/− and AdoRA3−/− mice ruled out any involvement of these AdoRs in the inhibitory effects of adenosine. LAK cells with genetically disrupted AdoRA2A were resistant to the inhibitory effects of adenosine, CADO and NECA. However, with extremely high concentrations of CADO or NECA, mild inhibition of LAK cytotoxicity was observed that was probably mediated via AdoRA2B signaling. Thus, by using pharmacological and genetic blockage of AdoRs, our results clearly indicate the prime importance of cAMP elevating AdoR2A in the inhibitory effect of adenosine on LAK cell cytotoxicity. The elevated intratumor levels of adenosine might inhibit the antitumor effects of activated NK cells.