bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neutrophil Serine Proteinases Activate Human Nonepithelial Cells to Produce Inflammatory Cytokines Through Protease-Activated Receptor 2
Authors: Uehara Akiko , Muramoto Koji , Takada Haruhiko , Sugawara Shunji 
Published: April 2014

Abstract
Protease-activated receptors (PARs) compose a family of G protein-coupled receptors activated by proteolysis with exposure of their tethered ligand. Recently, we reported that a neutrophil-derived serine proteinase, proteinase 3 (PR3), activated human oral epithelial cells through PAR-2. The present study examined whether other neutrophil serine proteinases, human leukocyte elastase (HLE), and cathepsin G (Cat G) activate nonepithelial cells, human gingival fibroblasts (HGF). HLE and Cat G as well as PR3 activated HGF to produce IL-8 and monocyte chemoattractant protein 1. Human oral epithelial cells but not HGF express mRNA and protein of secretory leukocyte protease inhibitor, an inhibitor of HLE and Cat G, and recombinant secretory leukocyte protease inhibitor clearly inhibited the activation of HGF induced by HLE and Cat G but not by PR3. HGF express PAR-1 and PAR-2 mRNA in the cells and the proteins on the cell surface. HLE and Cat G cleaved the peptide corresponding to the N terminus of PAR-2 with exposure of its tethered ligand. Treatment with trypsin, an agonist for PAR-2, and a synthetic PAR-2 agonist peptide induced intracellular Ca2+ mobilization and rendered cells refractory to subsequent stimulation with HLE and Cat G. The production of cytokine induced by HLE and Cat G and the PAR-2 agonist peptide was completely abolished by inhibition of phospholipase C. These findings suggest that neutrophil serine proteinases have equal ability to activate human nonepithelial cells through PAR-2 to produce inflammatory cytokines and may control a number of inflammatory processes such as periodontitis.
Synergistic Effect of TNF-α in Soluble VCAM-1-Induced Angiogenesis Through α4 Integrins
Authors: Nakao Shintaro , Kuwano Takashi , Ishibashi Tatsuro , Kuwano Michihiko , Ono Mayumi 
Published: April 2014

Abstract
In our present study we focused on soluble VCAM-1 (sVCAM-1)/α4 integrin-induced angiogenesis and found that this type of angiogenesis was mediated through p38 mitogen-activated protein kinase and focal adhesion kinase (FAK). HUVEC expressed both α4 and β1 integrins, and it was reported that expression of α4 integrin and its counterreceptor, sVCAM-1/VCAM-1, was enhanced in response to an inflammatory cytokine, TNF-α. In endothelial cells phosphorylation of p38 and FAK, but not that of extracellular signal-regulated kinase 1/2 was induced by sVCAM-1. Migration of endothelial cells was stimulated in response to sVCAM-1 at similar levels as those induced by vascular endothelial growth factor, and sVCAM-1-induced migration was almost completely blocked by neutralizing Ab against α4 integrin, by either an inhibitor of p38 (SB203580), or by adenovirus containing FAK-related nonkinase. sVCAM-1 also induced the formation of blood vessels in Matrigel plug assay in vivo, and this neovascularization was blocked by SB203580 or neutralizing Ab against α4 integrin. Moreover, we also confirmed that both TNF-α and sVCAM-1 could synergistically induce angiogenesis in the corneas of mice when each factor at used dose could not induce. This angiogenesis by TNF-α and sVCAM-1 was almost completely blocked by coadministration of SB203580 and also by neutralizing Ab against α4 integrin. These results suggest that sVCAM-1/α4 integrin induces angiogenesis through p38 and FAK signaling pathways.
T Cells of Atopic Asthmatics Preferentially Infiltrate Into Human Bronchial Xenografts in SCID Mice
Authors: Tsumori Kaori , Kohrogi Hirotsugu , Goto Eisuke , Hirata Naomi , Hirosako Susumu , Fujii Kazuhiko , Ando Makoto , Kawano Osamu , Mizuta Hiroshi 
Published: April 2014

Abstract
T cells play an important role in the pathogenesis of bronchial asthma. However, it is not completely known how circulating lymphocytes infiltrate into the airways of asthmatic patients. Because SCID mice are unable to reject xenogenic transplants, many xenotransplant models using various human tissues have been developed. Therefore, to examine the interaction between bronchi and T lymphocytes of asthma, it may be possible to use the human bronchial xenograft and PBMC xenograft in SCID mice. We transplanted human bronchi into the subcutaneum of SCID mice and i.p. injected PBMCs that were obtained from patients with atopic asthma, atopic dermatitis and rheumatoid arthritis, and normal subjects (asthmatic, dermatitis, rheumatic, and normal huPBMC-SCID mice). There was no difference in the percentage of CD3-, CD4-, CD8-, CD25-, CD45RO-, CD103-, and cutaneous lymphocyte Ag-positive cells in PBMCs among the patients with asthma, dermatitis, rheumatoid arthritis, and normal subjects, and CD3-positive cells in peripheral blood of asthmatic, dermatitis, rheumatic, and normal huPBMC-SCID mice. The number of CD3-, CD4-, and CD8-positive cells in the xenografts of asthmatic huPBMC-SCID mice was higher than those of dermatitis, rheumatic, and normal huPBMC-SCID mice. IL-4 mRNA and IL-5 mRNA were significantly higher in the xenografts of asthmatic huPBMC-SCID mice than those in the xenografts of normal huPBMC-SCID mice, but there were no significant differences in the expressions of IL-2 mRNA or IFN-γ mRNA between them. These findings suggest that T cells, especially Th2-type T cells, of asthmatics preferentially infiltrate into the human bronchi.
HIV-1 Replication Increases HIV-Specific CD4+ T Cell Frequencies but Limits Proliferative Capacity in Chronically Infected Children
Authors: Scott Zachary A. , Beaumier Coreen M. , Sharkey Mark , Stevenson Mario , Luzuriaga Katherine 
Published: April 2014

Abstract
This study investigated the relationship between HIV-1 replication and virus (HIV-1; CMV)-specific CD4+ T cell frequency and function in HIV-1-infected children. HIV-1 gag p55-specific CD4+ T cell IFN-γ responses were detected in the majority of children studied. p55-specific responses were detected less commonly and at lower frequencies in children with &lt;50 copies/ml plasma HIV-1 RNA than in children with active HIV-1 replication. In children with &lt;50 copies/ml plasma HIV-1, p55-specific responses were detected only in children with evidence of ongoing HIV-1 replication, indicating a direct relationship between HIV-1 replication and HIV-specific CD4+ T cell frequencies. In contrast, p55-specific proliferative responses were detected more frequently in children with &lt;50 copies/ml plasma HIV-1. CMV-specific CD4+ responses were more commonly detected and at higher frequencies in CMV-coinfected children with suppressed HIV-1 replication. The lack of HIV-specific CD4+ proliferative responses, along with the preservation of CMV-specific CD4+ responses in children with controlled HIV-1 replication, suggests that viral replication may have deleterious effects on HIV-1 and other virus-specific CD4+ responses. Vaccination to stimulate HIV-specific CD4+ T cell responses in these children may synergize with antiretroviral therapy to improve the long-term control of viral replication, and may perhaps allow the eventual discontinuation of antiretroviral therapy.
Regulatory T Cells Secreting IL-10 Dominate the Immune Response to EBV Latent Membrane Protein 1
Authors: Marshall Neil A. , Vickers Mark A. , Barker Robert N. 
Published: April 2014

AbstractViruses exploit a number of strategies to evade immune recognition. In this study, we describe a novel mechanism by which EBV, rather than avoiding detection, subverts the immune response by stimulating regulatory T cells that secrete IL-10. Human PBMC from all EBV-seropositive, but not -seronegative, donors responded to both purified latent membrane protein 1 and the corresponding immunodominant peptides with high levels of IL-10 secretion by CD4+ T cells. These IL-10 responses, characteristic of T regulatory 1 cells, inhibited T cell proliferation and IFN-γ secretion induced by both mitogen and recall Ag. It was confirmed that the inhibition was IL-10 dependent by the use of neutralizing Ab. The deviation of the immune response toward suppression is likely to be important in maintaining latency and EBV-associated tumors.
Fas (CD95) Induces Proinflammatory Cytokine Responses by Human Monocytes and Monocyte-Derived Macrophages
Authors: Park David R. , Thomsen Anni R. , Frevert Charles W. , Pham Uyenvy , Skerrett Shawn J. , Kiener Peter A. , Liles W. Conrad 
Published: April 2014

AbstractFas (CD95, APO-1) is regarded as the prototypical cell death receptor of the TNFR superfamily. Fas-induced apoptosis is generally considered to be a noninflammatory process, contributing to the silent resolution of immune and inflammatory responses. However, accumulating evidence indicates that Fas may also induce cellular activation signals. We hypothesized that Fas could activate proinflammatory cytokine responses by normal human monocytes and macrophages. Monocytes were isolated by negative immunoselection from the PBMC fraction of venous blood from healthy volunteers, and monocyte-derived macrophages were cultivated in vitro. Both monocytes and monocyte-derived macrophages released TNF-α and IL-8 following Fas ligation, and conditioned medium from Fas-activated monocytes and macrophages induced the directed migration of neutrophils in a chemotaxis assay. Fas-induced monocyte cytokine responses were associated with monocyte apoptosis, nuclear translocation of NF-κB, and cytokine gene expression and were blocked by caspase inhibition but not by inhibition of IL-1β signaling. In contrast, Fas-induced macrophage cytokine responses occurred in the absence of apoptosis and were caspase independent, indicating maturation-dependent differences in the Fas signaling pathways that lead to proinflammatory cytokine induction. Rather than contributing to the resolution of inflammation, Fas ligation on circulating monocytes and tissue macrophages may induce proinflammatory cytokine responses that can initiate acute inflammatory responses and tissue injury.
Novel Quantitative Trait Loci Controlling Development of Experimental Autoimmune Encephalomyelitis and Proportion of Lymphocyte Subpopulations
Authors: Karlsson Jenny , Zhao Xiangshan , Lonskaya Irina , Neptin Malin , Holmdahl Rikard , Andersson Åsa 
Published: April 2014

AbstractThe B10.RIII mouse strain (H-2r) develops chronic experimental autoimmune encephalomyelitis (EAE) upon immunization with the myelin basic protein 89–101 peptide. EAE was induced and studied in a backcross between B10.RIII and the EAE-resistant RIIIS/J strain (H-2r), and a complete genome scan with microsatellite markers was performed. Five loci were significantly linked to different traits and clinical subtypes of EAE on chromosomes 1, 5, 11, 15, and 16, three of the loci having sex specificity. The quantitative trait locus on chromosome 15 partly overlapped with the Eae2 locus, previously identified in crosses between the B10.RIII and RIIIS/J mouse strains. The loci on chromosomes 11 and 16 overlapped with Eae loci identified in other mouse crosses. By analyzing the backcross animals for lymphocyte phenotypes, the proportion of B and T cells in addition to the levels of CD4+CD8− and CD4−CD8+ T cells and the CD4+/CD8+ ratio in spleen were linked to different loci on chromosomes 1, 2, 3, 5, 6, 11, and 15. On chromosome 16, we found significant linkage to spleen cell proliferation. Several linkages overlapped with the quantitative trait loci for disease phenotypes. The identification of subphenotypes that are linked to the same loci as disease traits could be most useful in the search for candidate genes and biological pathways involved in the pathological process.
Cyclooxygenase-2 Expression by Nonsteroidal Anti-inflammatory Drugs in Human Airway Smooth Muscle Cells: Role of Peroxisome Proliferator-Activated Receptors
Authors: Pang Linhua , Nie Mei , Corbett Lisa , Knox Alan J. 
Published: April 2014

AbstractNonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to modulate cyclooxygenase (COX)-2 expression, but the mechanisms involved are controversial and may be cell specific. We show in this study that indomethacin (Indo), flurbiprofen (Flur), and the selective COX-2 inhibitor NS-398 induced COX-2 expression and markedly enhanced IL-1β-induced COX-2 expression in human airway smooth muscle (HASM) cells. These effects were not reversed by exogenous PGE2, suggesting that they are prostanoid-independent. Indeed, PGE2 also induced and enhanced IL-1β-induced COX-2 expression. Peroxisome proliferator-activated receptor (PPAR) α and PPARγ (not PPARβ) were expressed in HASM cells. PPARγ activators ciglitizone (Cig) and 15-Deoxy-Δ12,14-PGJ2 (15d-PGJ2), but not the PPARα activator WY-14643, mimicked the effect of NSAIDs on COX-2 expression. Treatment with Flur, NS-398, Cig, and 15d-PGJ2 alone, but not Indo and WY-14643, elevated COX activity; however, neither enhanced IL-1β-induced COX activity. Pretreatment with dexamethasone suppressed COX-2 expression, PGE2 release, and COX activity induced by NS-398, Cig, IL-1β, alone or in combination. Unlike IL-1β, NS-398 and Cig did not cause NF-κB (p65) nuclear translocation, nor did they further enhance IL-1β-induced NF-κB translocation, but they stimulated PPARγ translocation. Indo, NS-398, Flur, and 15d-PGJ2, but not WY-14643, induced transcriptional activity of a COX-2 reporter construct containing the peroxisome proliferator response element (PPRE) on their own and enhanced the effect of IL-1β, but had no effect on a COX-2 reporter construct lacking the PPRE. The results suggest that COX-2 expression by NSAIDs is biologically functional, prostanoid-independent, and involves PPARγ activation, and provide the first direct evidence that the PPRE in the promoter is required for NSAID-induced COX-2 expression.
New Loci Regulating Rat Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis
Authors: Becanovic Kristina , Wallstrom Erik , Kornek Barbara , Glaser Anna , Broman Karl W. , Dahlman Ingrid , Olofsson Peter , Holmdahl Rikard , Luthman Holger , Lassmann Hans , Olsson Tomas 
Published: April 2014

AbstractMyelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease in rats that closely mimics many clinical and histopathological aspects of multiple sclerosis. Non-MHC quantitative trait loci regulating myelin oligodendrocyte glycoprotein-induced EAE have previously been identified in the EAE-permissive strain, DA, on rat chromosomes 4, 10, 15, and 18. To find any additional gene loci in another well-known EAE-permissive strain and thereby to assess any genetic heterogeneity in the regulation of the disease, we have performed a genome-wide linkage analysis in a reciprocal (LEW.1AV1 × PVG.1AV1) male/female F2 population (n = 185). We examined reciprocal crosses, but no parent-of-origin effect was detected. The parental rat strains share the RT1av1 MHC haplotype; thus, non-MHC genes control differences in EAE susceptibility. We identified Eae16 on chromosome 8 and Eae17 on chromosome 13, significantly linked to EAE phenotypes. Two loci, on chromosomes 1 and 17, respectively showed suggestive linkage to clinical and histopathological EAE phenotypes. Eae16 and Eae17 differ from those found in previously studied strain combinations, thus demonstrating genetic heterogeneity of EAE. Furthermore, we detected a locus-specific parent-of-origin effect with suggestive linkage in Eae17. Further genetic and functional dissection of these loci may disclose critical disease-regulating molecular mechanisms.
Chemoattraction of Human T Cells by IL-18
Authors: Komai-Koma Mousa , Gracie J. Alastair , Wei Xiao-qing , Xu Damo , Thomson Neil , McInnes Iain B. , Liew Foo Y. 
Published: April 2014

AbstractCell locomotion is crucial to the induction of an effective immune response. We report here the chemoattraction of CD4+ T cells by IL-18, a member of the IL-1 cytokine family. Recombinant IL-18 increased the proportion of T cells in polarized morphology in vitro and stimulated their subsequent invasion into collagen gels in an IL-18 concentration gradient-dependent manner. Immunofluorescent microscopy studies determined that the major cell type responding to IL-18 was IL-18R+CD4+. Importantly, synovial CD4+ T cells from patients with rheumatoid arthritis responded to IL-18, adopting polarized morphology and gel invasion without further activation ex vivo, indicating the physiologic relevance of our observations. Finally, injection of rIL-18 into the footpad of DBA/1 mice led to local accumulation of inflammatory cells. These data therefore demonstrate for the first time lymphocyte chemoattractant properties of a member of the IL-1 cytokine family and its relevance in inflammatory diseases.
Diverse Repertoire of HIV-1 p24-Specific, IFN-γ-Producing CD4+ T Cell Clones Following Immune Reconstitution on Highly Active Antiretroviral Therapy
Authors: Boritz Eli , Palmer Brent E. , Livingston Brian , Sette Alessandro , Wilson Cara C. 
Published: April 2014

AbstractHIV-1 Ag-specific CD4+ T cell proliferative responses in human subjects with advanced, untreated HIV-1 disease are often weak or undetectable. Conversely, HIV-1-specific CD4+ T cell proliferation is occasionally detected following suppression of HIV-1 replication with highly active antiretroviral therapy (HAART). These observations suggest that unchecked HIV-1 replication may lead to depletion or dysfunction of HIV-1-specific CD4+ T cells, and that these defects may be partially corrected by viral suppression and subsequent immune reconstitution. However, the impact of this immune reconstitution on the repertoire of HIV-1-specific CD4+ T cells has not been thoroughly evaluated. To examine the HIV-1-specific CD4+ T cell repertoire in this clinical setting, we established HIV-1 p24-specific CD4+ T cell clones from a successfully HAART-treated subject whose pretreatment peripheral CD4 count was 0 cells/μl. Eleven different p24-specific CD4+ T cell clonotypes were distinguished among 13 clones obtained. Most clones produced both IFN-γ and IL-4 upon Ag stimulation. Clones targeted eight distinct epitopes that varied in their conservancy among HIV-1 strains, and responses were restricted by one of three MHC II molecules. Clones showed a range of functional avidities for both protein and peptide Ags. Additional studies confirmed that multiple HIV-1 p24-derived epitopes were targeted by IFN-γ-producing CD4+ cells from subjects first treated with HAART during advanced HIV-1 disease (median, 4.5 peptides/subject; range, 3–6). These results suggest that in HAART-treated subjects whose peripheral CD4+ T cell pools were once severely depleted, the HIV-1-specific CD4+ T cell repertoire may include a diverse array of clonotypes targeting multiple HIV-1 epitopes.
Decreased E12 and/or E47 Transcription Factor Activity in the Bone Marrow As Well As in the Spleen of Aged Mice
Authors: Frasca Daniela , Nguyen Diep , Riley Richard L. , Blomberg Bonnie B. 
Published: April 2014

AbstractThe E2A-encoded transcription factors E12 and E47 are key regulators of B cell functions. They bind to the E-box site, found in regulatory regions of B cell-specific genes; promote cell survival of early pre-B cells; help to initiate Ig rearrangements; and are also involved in class switch in mature B cells in the periphery. We have investigated the expression and function of E47 and E12 in IL-7-expanded pro-B/pre-B cell precursors and in unstimulated or LPS-activated splenic B cells from young and old BALB/c mice. Results show that B cell precursors from the bone marrow of old mice exhibit a reduced expression of E2A proteins and a reduced ability to bind DNA, as compared with young mice. In the spleen, E2A protein expression and DNA binding are present in unstimulated B cells from young mice and, to a significantly lesser extent, from old mice. These are both strongly induced by activation in splenic B cells from young mice but only moderately induced in old mice, indicating that aging affects the expression and activity of E2A-encoded genes and also that DNA binding correlates with the amount of protein expression. The levels of E2A DNA binding in the spleen correlate with those in the bone marrow for individual mice. In splenic mature B cells, only E47/E47 complexes bind DNA; whereas in bone marrow B cell precursors, E47/E12 complexes participate in DNA binding. Only nuclear extracts of splenic mature B cells, but both nuclear and cytoplasmic extracts of bone marrow B cell precursors, exhibit DNA binding.
CD4+ T Cells from Lupus-Prone Mice Avoid Antigen-Specific Tolerance Induction In Vivo
Authors: Bouzahzah Farida , Jung Sungsoo , Craft Joseph 
Published: April 2014

AbstractActivated T cells in spontaneous lupus presumably bypass normal tolerance mechanisms in the periphery, since thymic tolerance appears intact. To determine whether such T cells indeed avoid in vivo peripheral tolerance mechanisms, we assessed their activation and recall responses after in vivo Ag stimulation in the absence of exogenously supplied costimulatory signals. Naive CD4+ AND (transgenic mice bearing rearranged TCR specific for pigeon cytochrome c, peptides 88–104) TCR-transgenic T cells, specific for pigeon cytochrome c, from lupus-prone Fas-intact MRL/Mp+Fas-lpr and from H-2k-matched control CBA/CaJ and B10.BR mice (MRL.AND, CBA.AND, and B10.AND, respectively) were adoptively transferred into (MRL × CBA)F1 or (MRL × B10)F1 recipients transgenically expressing membrane-bound pigeon cytochrome c as a self-Ag. MRL.AND and control CBA.AND and B10.AND-transgenic T cells were activated and divided after transfer, indicating encounter with their cognate Ag; however, T cells from CBA.AND and B10.AND mice were impaired in their ability to proliferate and produce IL-2 after challenge with pigeon cytochrome c in ex vivo recall assays, a typical phenotype of anergized cells. By contrast, MRL.AND T cells proliferated more, and a significantly higher percentage of such cells produced IL-2, compared with control T cells. This observation that MRL T cells avoided anergy induction in vivo was confirmed in an in vitro system where the cells were stimulated with an anti-CD3 in the absence of a costimulatory signal. These experiments provide direct evidence that CD4+ T cells from Fas-intact lupus-prone MRL mice are more resistant than nonautoimmune control cells to anergy induction. Anergy avoidance in the periphery might contribute to the characteristic finding in lupus of inappropriate T cell activation in response to ubiquitous self-Ags.