bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcription Factor Tfec Contributes to the IL-4-Inducible Expression of a Small Group of Genes in Mouse Macrophages Including the Granulocyte Colony-Stimulating Factor Receptor
Authors: Rehli Michael , Sulzbacher Sabine , Pape Sabine , Ravasi Timothy , Wells Christine A. , Heinz Sven , Söllner Liane , El Chartouni Carol , Krause Stefan W. , Steingrimsson Eirikur , Hume David A. , Andreesen Reinhard 
Published: April 2014

AbstractExpression of the mouse transcription factor EC (Tfec) is restricted to the myeloid compartment, suggesting a function for Tfec in the development or function of these cells. However, mice lacking Tfec develop normally, indicating a redundant role for Tfec in myeloid cell development. We now report that Tfec is specifically induced in bone marrow-derived macrophages upon stimulation with the Th2 cytokines, IL-4 and IL-13, or LPS. LPS induced a rapid and transient up-regulation of Tfec mRNA expression and promoter activity, which was dependent on a functional NF-κB site. IL-4, however, induced a rapid, but long-lasting, increase in Tfec mRNA, which, in contrast to LPS stimulation, also resulted in detectable levels of Tfec protein. IL-4-induced transcription of Tfec was absent in macrophages lacking Stat6, and its promoter depended on two functional Stat6-binding sites. A global comparison of IL-4-induced genes in both wild-type and Tfec mutant macrophages revealed a surprisingly mild phenotype with only a few genes affected by Tfec deficiency. These included the G-CSFR (Csf3r) gene that was strongly up-regulated by IL-4 in wild-type macrophages and, to a lesser extent, in Tfec mutant macrophages. Our study also provides a general definition of the transcriptome in alternatively activated mouse macrophages and identifies a large number of novel genes characterizing this cell type.
Sex-Specific Effect of Insulin-Dependent Diabetes 4 on Regulation of Diabetes Pathogenesis in the Nonobese Diabetic Mouse
Authors: Ivakine Evgueni A. , Fox Casey J. , Paterson Andrew D. , Mortin-Toth Steven M. , Canty Angelo , Walton David S. , Aleksa Katarina , Ito Shinya , Danska Jayne S. 
Published: April 2014

Abstract
Many human autoimmune diseases are more frequent in females than males, and their clinical severity is affected by sex hormone levels. A strong female bias is also observed in the NOD mouse model of type I diabetes (T1D). In both NOD mice and humans, T1D displays complex polygenic inheritance and T cell-mediated autoimmune pathogenesis. The identities of many of the insulin-dependent diabetes (Idd) loci, their influence on specific stages of autoimmune pathogenesis, and sex-specific effects of Idd loci in the NOD model are not well understood. To address these questions, we analyzed cyclophosphamide-accelerated T1D (CY-T1D) that causes disease with high and similar frequencies in male and female NOD mice, but not in diabetes-resistant animals, including the nonobese diabetes-resistant (NOR) strain. In this study we show by genetic linkage analysis of (NOD × NOR) × NOD backcross mice that progression to severe islet inflammation after CY treatment was controlled by the Idd4 and Idd9 loci. Congenic strains on both the NOD and NOR backgrounds confirmed the roles of Idd4 and Idd9 in CY-T1D susceptibility and revealed the contribution of a third locus, Idd5. Importantly, we show that the three loci acted at distinct stages of islet inflammation and disease progression. Among these three loci, Idd4 alleles alone displayed striking sex-specific behavior in CY-accelerated disease. Additional studies will be required to address the question of whether a sex-specific effect of Idd4, observed in this study, is also present in the spontaneous model of the disease with striking female bias.
Dendritic Cell-Intrinsic Expression of NF-κB1 Is Required to Promote Optimal Th2 Cell Differentiation
Authors: Artis David , Kane Colleen M. , Fiore James , Zaph Colby , Shapira Sagi , Joyce Karen , MacDonald Andrew , Hunter Christopher , Scott Phillip , Pearce Edward J. 
Published: April 2014

Abstract
A number of receptors and signaling pathways can influence the ability of dendritic cells (DC) to promote CD4+ Th type 1 (Th1) responses. In contrast, the regulatory pathways and signaling events that govern the ability of DC to instruct Th2 cell differentiation remain poorly defined. In this report, we demonstrate that NF-κB1 expression within DC is required to promote optimal Th2 responses following exposure to Schistosoma mansoni eggs, a potent and natural Th2-inducing stimulus. Although injection of S. mansoni eggs induced production of IL-4, IL-5, and IL-13 in the draining lymph node of wild-type (WT) mice, NF-κB1−/− hosts failed to express Th2 cytokines and developed a polarized Ag-specific IFN-γ response. In an in vivo adoptive transfer model in which NF-κB-sufficient OVA-specific DO11.10 TCR transgenic T cells were injected into OVA-immunized WT or NF-κB1−/− hosts, NF-κB1−/− APCs efficiently promoted CD4+ T cell proliferation and IFN-γ responses, but failed to promote Ag-specific IL-4 production. Further, bone marrow-derived DC from NF-κB1−/− mice failed to promote OVA-specific Th2 cell differentiation in in vitro coculture studies. Last, S. mansoni egg Ag-pulsed NF-κB1−/− DC failed to prime for Th2 cytokine responses following injection into syngeneic WT hosts. Impaired Th2 priming by NF-κB1−/− DC was accompanied by a reduction in MAPK phosphorylation in Ag-pulsed DC. Taken together, these studies identify a novel requirement for DC-intrinsic expression of NF-κB1 in regulating the MAPK pathway and governing the competence of DC to instruct Th2 cell differentiation.
Neutralizing Antibodies to Adenovirus Serotype 5 Vaccine Vectors Are Directed Primarily against the Adenovirus Hexon Protein
Authors: Sumida Shawn M. , Truitt Diana M. , Lemckert Angelique A. C. , Vogels Ronald , Custers Jerome H. H. V. , Addo Marylyn M. , Lockman Shahin , Peter Trevor , Peyerl Fred W. , Kishko Michael G. , Jackson Shawn S. , Gorgone Darci A. , Lifton Michelle A. , Essex Myron , Walker Bruce D. , Goudsmit Jaap , Havenga Menzo J. E. , Barouch Dan H. 
Published: April 2014

Abstract
The utility of recombinant adenovirus serotype 5 (rAd5) vector-based vaccines for HIV-1 and other pathogens will likely be limited by the high prevalence of pre-existing Ad5-specific neutralizing Abs (NAbs) in human populations. However, the immunodominant targets of Ad5-specific NAbs in humans remain poorly characterized. In this study, we assess the titers and primary determinants of Ad5-specific NAbs in individuals from both the United States and the developing world. Importantly, median Ad5-specific NAb titers were &gt;10-fold higher in sub-Saharan Africa compared with the United States. Moreover, hexon-specific NAb titers were 4- to 10-fold higher than fiber-specific NAb titers in these cohorts by virus neutralization assays using capsid chimeric viruses. We next performed adoptive transfer studies in mice to evaluate the functional capacity of hexon- and fiber-specific NAbs to suppress the immunogenicity of a prototype rAd5-Env vaccine. Hexon-specific NAbs were remarkably efficient at suppressing Env-specific immune responses elicited by the rAd5 vaccine. In contrast, fiber-specific NAbs exerted only minimal suppressive effects on rAd5 vaccine immunogenicity. These data demonstrate that functionally significant Ad5-specific NAbs are directed primarily against the Ad5 hexon protein in both humans and mice. These studies suggest a potential strategy for engineering novel Ad5 vectors to evade dominant Ad5-specific NAbs.
Up-Regulation of the JAK/STAT1 Signal Pathway during Chlamydia trachomatis Infection
Authors: Lad Sonya P. , Fukuda Elaine Y. , Li Jiali , de la Maza Luis M. , Li Erguang 
Published: April 2014

Abstract
Chlamydia trachomatis infection is the most common cause of sexually transmitted disease, leading to female pelvic inflammatory disease and infertility. The disease process has been linked to cellular response to this bacterial pathogen. This obligate intracellular pathogen infects macrophages, fibroblast cells, and epithelial and endothelial cells. We show in this study that infection of cervical epithelial cells, the primary target of Chlamydia trachomatis, leads to up-regulation and activation of the JAK/STAT signal pathway. Specifically, Chlamydia trachomatis infection of HeLa 229 cells selectively induces STAT1, STAT2, and IFN-stimulated transcription factor 3γ expression and promotes STAT1 activation. The up-regulation of STAT1 is dependent on bacterial replication, because treatment of infected cells with antibiotics prevents STAT1 up-regulation. By analysis of the gene transcriptional and cytokine expression profiles of host cells combined with the use of neutralizing Abs, we show that IFN-β production is critical for STAT1 induction in epithelial cells. Finally, we demonstrate that the host up-regulates STAT1 to restrict bacterial infection, because Chlamydia propagates more efficiently in STAT1-null or STAT1 knockdown cells, whereas Chlamydia growth is inhibited in cells with up-regulated STAT1 expression. This study demonstrates that the infected cells up-regulate the host innate antimicrobial response to chlamydial infection. It also highlights the importance of cellular response by nonimmune cells in host clearance of chlamydial infection.
Immune-Reconstituted Influenza Virosome Containing CD40L Gene Enhances the Immunological and Protective Activity of a Carcinoembryonic Antigen Anticancer Vaccine
Authors: Cusi Maria Grazia , Del Vecchio Maria Teresa , Terrosi Chiara , Savellini Gianni Gori , Di Genova Giuseppa , La Placa Marco , Fallarino Francesca , Moser Christian , Cardone Concetta , Giorgi Giorgio , Francini Guido , Correale Pierpaolo 
Published: April 2014

Abstract
The correct interaction of a costimulatory molecule such as CD40L with its contrareceptor CD40 expressed on the membrane of professional APCs, provides transmembrane signaling that leads to APC activation. This process can be exploited to significantly improve the efficacy of cancer vaccines and the outcome of a possible cancer vaccine-induced, Ag-specific CTL response. Therefore, we investigated whether a novel intranasal delivery of immune-reconstituted influenza virosomes (IRIV), assembled with the CD40L gene (CD40L/IRIV), could be used to improve protective immunity and the Ag-specific CTL response against carcinoembryonic Ag (CEA) generated with a novel vaccine constituted of IRIV assembled with the CEA gene (CEA/IRIV). Our results suggest that CD40L/IRIV was able to augment CEA-specific CTL activity and CEA-specific protective immunity induced by CEA/IRIV most likely through the induction of a CTL response associated with a Th1 phenotype. In conclusion, we provide evidence that CD40L/IRIV, by acting through the CD40L/CD40 signaling pathway, acts as an immune-adjuvant that could increase the efficacy of a CEA-specific cancer vaccine, which could provide an efficacious new strategy for cancer therapy.
A Lymphotoxin-IFN-β Axis Essential for Lymphocyte Survival Revealed during Cytomegalovirus Infection
Authors: Banks Theresa A. , Rickert Sandra , Benedict Chris A. , Ma Lisa , Ko Mira , Meier Joshua , Ha Won , Schneider Kirsten , Granger Steven W. , Turovskaya Olga , Elewaut Dirk , Otero Dennis , French Anthony R. , Henry Stanley C. , Hamilton John D. , Scheu Stefanie , Pfeffer Klaus , Ware Carl F. 
Published: April 2014

Abstract
The importance of lymphotoxin (LT) βR (LTβR) as a regulator of lymphoid organogenesis is well established, but its role in host defense has yet to be fully defined. In this study, we report that mice deficient in LTβR signaling were highly susceptible to infection with murine CMV (MCMV) and early during infection exhibited a catastrophic loss of T and B lymphocytes, although the majority of lymphocytes were themselves not directly infected. Moreover, bone marrow chimeras revealed that lymphocyte survival required LTα expression by hemopoietic cells, independent of developmental defects in lymphoid tissue, whereas LTβR expression by both stromal and hemopoietic cells was needed to prevent apoptosis. The induction of IFN-β was also severely impaired in MCMV-infected LTα−/− mice, but immunotherapy with an agonist LTβR Ab restored IFN-β levels, prevented lymphocyte death, and enhanced the survival of these mice. IFN-αβR−/− mice were also found to exhibit profound lymphocyte death during MCMV infection, thus providing a potential mechanistic link between type 1 IFN induction and lymphocyte survival through a LTαβ-dependent pathway important for MCMV host defense.
Fc- and Complement-Receptor Activation Stimulates Cell Cycle Progression of Macrophage Cells from G1 to S
Authors: Luo Yong , Tucker Stephanie C. , Casadevall Arturo 
Published: April 2014

Abstract
Phagocytosis of microorganisms by macrophages is an important host defense mechanism. While studying the phagocytosis of the human pathogenic fungus Cryptococcus neoformans, we noted that macrophage-like J774 cells with ingested fungal cells had frequent mitotic figures. By analyzing the relative proportion of phagocytic cells as a function of cell cycle phase, we observed an increase in S phase cells after Fc-mediated phagocytosis of polystyrene beads, live or heat-killed C. neoformans. This result was confirmed by increased nuclear BrdU incorporation after Fc-mediated phagocytosis. The induced progression to S phase was observed after both Fc- and complement-mediated phagocytosis of live yeasts. Fc-mediated stimulation of cell division did not require ingestion, because it could be triggered by incubating cells in IgG1-coated plates. Phagocytosis-mediated stimulation of replication was confirmed in vitro using primary bone marrow macrophages and in vivo for peritoneal macrophages. We conclude that phagocytosis of microbes or inert particles can stimulate macrophages to enter S phase and commence cell division. This observation suggests a potential mechanism for increasing the number of effector cells after microbial ingestion, but can also promote the spread of infection.
Astrocyte-Derived ATP Induces Vesicle Shedding and IL-1β Release from Microglia
Authors: Bianco Fabio , Pravettoni Elena , Colombo Alessio , Schenk Ursula , Möller Thomas , Matteoli Michela , Verderio Claudia 
Published: April 2014

Abstract
ATP has been indicated as a primary factor in microglial response to brain injury and inflammation. By acting on different purinergic receptors 2, ATP is known to induce chemotaxis and stimulate the release of several cytokines from these cells. The activation of purinergic receptors 2 in microglia can be triggered either by ATP deriving from dying cells, at sites of brain injury or by ATP released from astrocytes, in the absence of cell damage. By the use of a biochemical approach integrated with video microscopy experiments, we investigated the functional consequences triggered in microglia by ATP released from mechanically stimulated astrocytes, in mixed glial cocultures. Astrocyte-derived ATP induced in nearby microglia the formation and the shedding of membrane vesicles. Vesicle formation was inhibited by the ATP-degrading enzyme apyrase or by P2X7R antagonists. Isolation of shed vesicles, followed by IL-1β evaluation by a specific ELISA revealed the presence of the cytokine inside the vesicular organelles and its subsequent efflux into the extracellular medium. IL-1β efflux from shed vesicles was enhanced by ATP stimulation and inhibited by pretreatment with the P2X7 antagonist oxidized ATP, thus indicating a crucial involvement of the pore-forming P2X7R in the release of the cytokine. Our data identify astrocyte-derived ATP as the endogenous factor responsible for microvesicle shedding in microglia and reveal the mechanisms by which astrocyte-derived ATP triggers IL-1β release from these cells.
Long-Term Exposure of the HT-29 Human Intestinal Epithelial Cell Line to TNF Causes Sustained Up-Regulation of the Polymeric Ig Receptor and Proinflammatory Genes through Transcriptional and Posttranscriptional Mechanisms
Authors: Bruno Maria E. C. , Kaetzel Charlotte S. 
Published: April 2014

Abstract
Transport of IgA Abs across intestinal epithelial cells into gut secretions is mediated by the polymeric Ig receptor (pIgR). The cytokine TNF plays a central role in initiating and amplifying inflammatory reactions, and is implicated in the pathogenesis of inflammatory bowel diseases. Acute exposure of intestinal epithelial cell lines to TNF has been shown to up-regulate transcription of genes encoding pIgR and a number of proinflammatory factors, but the effects of chronic exposure to TNF have not been studied. We found that exposure of HT-29 human colon carcinoma cells to TNF for up to 20 days reduced the rate of cell proliferation, but did not cause gross morphological changes. Expression of mRNA encoding pIgR and several proinflammatory genes increased acutely, and then diminished but remained elevated above control levels throughout the experiment. Changes in gene expression were paralleled by increased expression of the transcription factors IFN regulatory factor-1 and the RelB subunit of NF-κB. HT-29 cells activated the endogenous TNF gene in response to TNF treatment, but the level of TNF production was insufficient to maintain pIgR and proinflammatory gene expression after withdrawal of exogenous TNF. Chronic exposure to TNF caused a marked increase in pIgR mRNA stability and a small but significant decrease in TNF mRNA stability, but no change in the half-lives of IL-8, c-Myc, and GAPDH. In summary, we observed different effects of acute vs chronic exposure to TNF on gene expression, and found evidence for transcriptional and posttranscriptional regulation of expression of the pIgR.
Cell-Based Immunotherapy with Suppressor CD8+ T Cells in Rheumatoid Arthritis
Authors: Davila Eduardo , Kang Young Mo , Park Yong Wook , Sawai Hirokazu , He Xiaowen , Pryshchep Sergey , Goronzy Jörg J. , Weyand Cornelia M. 
Published: April 2014

Abstract
The chronic persistence of rheumatoid synovitis, an inflammation driven by activated T cells, macrophages, and fibroblasts causing irreversible joint damage, suggests a failure in physiologic mechanisms that down-regulate and terminate chronic immune responses. In vitro CD8+CD28−CD56+ T cells tolerize APCs, prevent the priming of naive CD4+ T cells, and suppress memory CD4+ T cell responses. Therefore, we generated CD8+CD28−CD56+ T cell clones from synovial tissues, expanded them in vitro, and adoptively transferred them into NOD-SCID mice engrafted with synovial tissues from patients with rheumatoid arthritis. Adoptively transferred CD8+CD28−CD56+ T cells displayed strong anti-inflammatory activity. They inhibited production of IFN-γ, TNF-α, and chemokines in autologous and HLA class I-matched heterologous synovitis. Down-regulation of costimulatory ligands CD80 and CD86 on synovial fibroblasts was identified as one mechanism of immunosuppression. We propose that rheumatoid synovitis can be suppressed by cell-based immunotherapy with immunoregulatory CD8+ T cells.
Interference with the IL-1-Signaling Pathway Improves the Toxicity Profile of Systemically Applied Adenovirus Vectors
Authors: Shayakhmetov Dmitry M. , Li Zong-Yi , Ni Shaoheng , Lieber André 
Published: April 2014

Abstract
The safety of gene therapy vectors is a major concern when novel viral or nonviral therapeutics are proposed for applications in humans. Adenovirus (Ad) vectors have been extensively used as efficient gene delivery vehicles in vitro over the last two decades. However, upon i.v. application, they elicit robust innate and inflammatory responses that may be fatal for the host. To date, the primary cytokines and chemokines involved in the initiation of these host responses remain illusive. In this study, we demonstrate that IL-1 is a major mediator involved in the initiation of immediate host responses toward i.v. applied Ad vectors. Using mice in which IL-1 signaling was genetically eliminated (IL-1RI-KO), or wild-type animals for which signaling was blocked by anti-IL-1 Abs, we found that i.v. applied Ad vectors elicited dramatically reduced acute inflammatory responses when compared with control animals. Importantly, the efficiency of Ad gene transfer in vivo was not significantly affected by interfering with IL-1 signaling. Using an in situ hybridization technique, we found that hepatocytes and Kupffer cells trigger IL-1 transcription in liver tissue after i.v. Ad vector administration. We also found that expression of the MIP-2 chemokine gene (which is responsible for recruitment of neutrophils to the liver) depends on IL-1 activation. Our data indicate that immediate innate and inflammatory host responses toward i.v. applied Ad vectors can be pharmacologically controlled through interference with IL-1 signaling pathways.
Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection
Authors: Noorbakhsh Farshid , Vergnolle Nathalie , McArthur Justin C. , Silva Claudia , Vodjgani Mohammed , Andrade-Gordon Patricia , Hollenberg Morley D. , Power Christopher 
Published: April 2014

Abstract
Proteinase-activated receptors (PARs), a newly discovered subgroup of G-protein coupled receptors, are widely expressed by neural cells, but their roles in the nervous system remain uncertain. In this study, we report that PAR-2 was up-regulated on neurons in conjunction with neuroinflammation in brain tissue from patients with HIV-1-associated dementia. The inflammatory cytokines TNF-α and IL-1β were also increased in HIV-1-associated dementia brains compared with patients without dementia (p &lt; 0.05), but these same cytokines induced PAR-2 expression on neurons. Enhanced PAR-2 expression and subsequent activation prevented neuronal cell death and induction of the tumor suppressor, p53, caused by the HIV-encoded protein, Tat (p &lt; 0.01). Intrastriatal implantation of a PAR-2 peptide agonist also inhibited Tat-induced neurotoxicity in a mouse model of HIV neuropathogenesis (p &lt; 0.05). Moreover, PAR-2 null animals showed more severe neuroinflammation and neuronal loss caused by Tat neurotoxicity (p &lt; 0.05). TNF-α protected wild-type neurons from Tat-related neurotoxicity, but in PAR-2-deficient neurons, the same concentrations of TNF-α were cytotoxic (p &lt; 0.001). Thus, neuroinflammation can exert protective effects by which it induces PAR-2 expression with the ensuing abrogation of neuronal death.