bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cross-Talk between ICAM-1 and GM-CSF Receptor Signaling Modulates Eosinophil Survival and Activation
Authors: Pazdrak Konrad , Young Travis W. , Stafford Susan , Olszewska-Pazdrak Barbara , Straub Christof , Starosta Vitaliy , Brasier Allan , Kurosky Alexander 
Published: April 2014

Abstract
Reversal of eosinophilic inflammation has been an elusive therapeutic goal in the management of asthma pathogenesis. In this regard, GM-CSF is a primary candidate cytokine regulating eosinophil activation and survival in the lung; however, its molecular mechanism of propagation and maintenance of stimulated eosinophil activation is not well understood. In this study, we elucidate those late interactions occurring between the GM-CSF receptor and activated eosinophil signaling molecules. Using coimmunoprecipitation with GM-CSF-stimulated eosinophils, we have identified that the GM-CSF receptor β-chain (GMRβ) interacted with ICAM-1 and Shp2 phosphatase, as well as Slp76 and ADAP adaptor proteins. Separate experiments using affinity binding with a tyrosine-phosphorylated peptide containing an ITIM (ICAM-1 residues 480–488) showed binding to Shp2 phosphatase and GMRβ. However, the interaction of GMRβ with the phosphorylated ICAM-1-derived peptide was observed only with stimulated eosinophil lysates, suggesting that the interaction of GMRβ with ICAM-1 required phosphorylated Shp2 and/or phosphorylated GMRβ. Importantly, we found that inhibition of ICAM-1 in activated eosinophils blocked GM-CSF-induced expression of c-fos, c-myc, IL-8, and TNF-α. Moreover, inhibition of ICAM-1 expression with either antisense oligonucleotide or an ICAM-1-blocking Ab effectively inhibited ERK activation and eosinophil survival. We concluded that the interaction between ICAM-1 and the GM-CSF receptor was essential for GM-CSF-induced eosinophil activation and survival. Taken together, these results provide novel mechanistic insights defining the interaction between ICAM-1 and the GM-CSF receptor and highlight the importance of targeting ICAM-1 and GM-CSF/IL-5/IL-3 receptor systems as a therapeutic strategy to counter eosinophilia in asthma.
Dual Modulation of Airway Smooth Muscle Contraction by Th2 Cytokines via Matrix Metalloproteinase-1 Production
Authors: Ohta Yoshinori , Hayashi Masayuki , Kanemaru Takaaki , Abe Kihachiro , Ito Yushi , Oike Masahiro 
Published: April 2014

Abstract
Altered contractility of airway smooth muscle (SM) is one of the main causes of allergic asthma, in which the predominance of Th2 over Th1 cytokines plays a central role. In the present study, we examine the effects of Th2 cytokines on airway SM contraction. Treatment with a low concentration of IL-4 (0.2 ng/ml) for 6 h augmented, whereas higher concentrations (2–20 ng/ml) inhibited, agonist-induced contractions of collagen gels containing bovine tracheal SM cells. Another Th2 cytokine (IL-13) showed an augmentation of gel contraction in the concentration range of 20–200 ng/ml. IL-4 and IL-13 increased mRNA expression and protein secretion of matrix metalloproteinase (MMP)-1, but these cytokines did not affect Ca2+-mobilizing properties and phosphorylation levels of myosin L chain in bovine tracheal SM cells. These changes were sensitive to wortmannin, an inhibitor of PI3K, but not to leflunomide, an inhibitor of STAT6. Scanning electron microscope observation revealed that collagen fibers twining around SM cells were completely dissolved in 20 ng/ml IL-4-treated gels and reorganized into basket-like structure in 20 ng/ml IL-13-treated gels. Exogenous application of high and low concentrations of MMP-1 also induced the inhibition and augmentation of gel contraction, respectively. Furthermore, nonselective MMP inhibitor galardin suppressed the effects of IL-4 and IL-13 on gel contraction, and MMP-1-targeted small-interfering RNA reversed the inhibitory effects of IL-4 on gel contraction to the augmentation. This indicates that Th2 cytokines modulate airway contraction without affecting cellular contractility but by secreting MMP-1 from the SM cells via PI3K activation and changing cell-to-matrix interactions.
STAT-1 Signaling in Human Lung Fibroblasts Is Induced by Vanadium Pentoxide through an IFN-β Autocrine Loop
Authors: Antao-Menezes Aurita , Turpin Elizabeth A. , Bost Phillip C. , Ryman-Rasmussen Jessica P. , Bonner James C. 
Published: April 2014

Abstract
The inhalation of vanadium pentoxide (V2O5) results in bronchitis and airway fibrosis. The lung fibrotic response to V2O5 partially resolves where fibroblasts first proliferate and deposit collagen, but then undergo growth arrest and apoptosis. STAT-1 mediates fibroblast growth arrest and apoptosis. We previously reported that STAT-1 is a protective factor and mice lacking STAT-1 are more susceptible to lung fibrosis. We also reported that V2O5-induced STAT-1 phosphorylation in lung fibroblasts requires H2O2 and de novo protein synthesis. In this study, we identified IFN-β as the protein that mediates STAT-1 activation by V2O5 in normal human lung fibroblasts and identified NADPH and xanthine oxidase systems as sources of H2O2 that drive IFN-β gene expression. STAT-1 phosphorylation was decreased with neutralizing Abs to IFN-β as well as an inhibitor of JAK. V2O5 also increased transcription of an IFN-inducible and STAT-1-dependent chemokine, CXCL10. Inhibition of H2O2-generating enzyme systems NADPH oxidase by apocynin and xanthine oxidase by allopurinol individually reduced STAT-1 phosphorylation. Apocynin and allopurinol also decreased V2O5-induced IFN-β mRNA levels and CXCL10 expression. IFN-α transcription was inhibited only by allopurinol. Taken together, these data indicate that fibroblasts play a role in the innate immune response to vanadium-induced oxidative stress by synthesizing IFN-β and activating STAT-1 to cause growth arrest and increase levels of CXCL10, a potent antifibrotic factor. This mechanism is postulated to counterbalance profibrogenic mechanisms that follow V2O5 injury.
Genetic Analysis of the Role of the PI3K-Akt Pathway in Lipopolysaccharide-Induced Cytokine and Tissue Factor Gene Expression in Monocytes/Macrophages
Authors: Luyendyk James P. , Schabbauer Gernot A. , Tencati Michael , Holscher Todd , Pawlinski Rafal , Mackman Nigel 
Published: April 2014

Abstract
LPS stimulation of monocytes/macrophages induces the expression of genes encoding proinflammatory cytokines and the procoagulant protein, tissue factor. Induction of these genes is mediated by various signaling pathways, including mitogen-activated protein kinases, and several transcription factors, including Egr-1, AP-1, ATF-2, and NF-κB. We used a genetic approach to determine the role of the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) pathway in the regulation of LPS signaling and gene expression in isolated macrophages and in mice. The PI3K-Akt pathway is negatively regulated by the phosphatase and tensin homologue (PTEN). We used peritoneal exudate cells from Pik3r1-deficient mice, which lack the p85α regulatory subunit of PI3K and have reduced PI3K activity, and peritoneal macrophages from PTENflox/flox/LysMCre mice (PTEN−/−), which have increased Akt activity. Analysis of LPS signaling in Pik3r1−/− and PTEN−/− cells indicated that the PI3K-Akt pathway inhibited activation of the ERK1/2, JNK1/2, and p38 mitogen-activated protein kinases and reduced the levels of nuclear Egr-1 protein and phosphorylated ATF-2. Modulating the PI3K-Akt pathway did not affect LPS-induced degradation of IκBα or NF-κB nuclear translocation. LPS induction of TNF-α, IL-6, and tissue factor gene expression was increased in Pik3r1−/− peritoneal exudate cells and decreased in PTEN−/− peritoneal macrophages compared with wild-type (WT) cells. Furthermore, LPS-induced inflammation and coagulation were enhanced in WT mice containing Pik3r1−/− bone marrow compared with WT mice containing WT bone marrow and in mice lacking the p85α subunit in all cells. Taken together, our results indicate that the PI3K-Akt pathway negatively regulates LPS signaling and gene expression in monocytes/macrophages.
A Helminth Immunomodulator Reduces Allergic and Inflammatory Responses by Induction of IL-10-Producing Macrophages
Authors: Schnoeller Corinna , Rausch Sebastian , Pillai Smitha , Avagyan Angela , Wittig Bianca M. , Loddenkemper Christoph , Hamann Alf , Hamelmann Eckard , Lucius Richard , Hartmann Susanne 
Published: April 2014

Abstract
The coincidence between infections with parasitic worms and the reduced prevalence of allergic disease in humans and in animal models has prompted the search for helminth molecules with antiallergic and antiinflammatory potential. We report herein that filarial cystatin, a secreted protease inhibitor of filarial nematodes, suppresses Th2-related inflammation and the ensuing asthmatic disease in a murine model of OVA-induced allergic airway responsiveness. Treatment with recombinant filarial cystatin inhibited eosinophil recruitment, reduced levels of OVA-specific and total IgE, down-regulated IL-4 production, and suppressed allergic airway hyperreactivity when applied during or after sensitization and before challenge with the allergen. Depletion of macrophages by clodronate-containing liposomes prevented the curative effects and restored the levels of infiltrating cells, IgE, and allergic airway reactivity. Blocking of IL-10 by application of anti-IL-10 receptor Abs restored the reduced number of infiltrating cells and the levels of OVA-specific IgE. In contrast, depletion of regulatory T cells by anti-CD25 Abs had only limited effects. Cystatin also modulated macrophage-mediated inflammation in a murine model of dextran sulfate sodium-induced colitis, leading to reduction of inflammatory infiltrations and epithelial damage. Our data demonstrate that treatment with a single helminth protein can exert the antiallergic effects of helminth infections.
A Critical Role for ABCG1 in Macrophage Inflammation and Lung Homeostasis
Authors: Wojcik Allison J. , Skaflen Marcus D. , Srinivasan Suseela , Hedrick Catherine C. 
Published: April 2014

Abstract
ATP-binding cassette transporter G1 (ABCG1) effluxes cholesterol from macrophages and plays an important role in pulmonary lipid homeostasis. We hypothesize that macrophages from Abcg1−/− mice have increased inflammatory activity, thereby promoting acceleration of pulmonary disease. We herein demonstrate increased numbers of inflammatory cytokines and infiltrating neutrophils, eosinophils, dendritic cells, T cells, and B cells into lungs of Abcg1−/− mice before the onset of severe lipidosis. We further investigated the role of macrophages in causing pulmonary disease by performing bone marrow transplantations using B6 and Abcg1−/− bone marrow. We found that it was the macrophage, and not pneumocyte type II cells or other nonhematopoietic cells in the lung, that appeared to be the primary cell type involved in the onset of both pulmonary lipidosis and inflammation in the Abcg1−/− mice. Additionally, our results demonstrate that Abcg1−/− macrophages had elevated proinflammatory cytokine production, increased apoptotic cell clearance, and were themselves more prone to apoptosis and necrosis. However, they were quickly repopulated by monocytes that were recruited to Abcg1−/− lungs. In conclusion, we have shown that ABCG1 deletion in macrophages causes a striking inflammatory phenotype and initiates onset of pulmonary lipidosis in mice. Thus, our studies reveal a critical role for macrophage ABCG1 in lung inflammation and homeostasis.
Delivery of Biologically Active Anti-Inflammatory Cytokines IL-10 and IL-1ra In Vivo by the Shigella Type III Secretion Apparatus
Authors: Chamekh Mustapha , Phalipon Armelle , Quertainmont Renaud , Salmon Isabelle , Sansonetti Philippe , Allaoui Abdelmounaaïm 
Published: April 2014

Abstract
Pathogenicity of many Gram-negative bacteria relies on a type III secretion (T3S) apparatus, which is used for delivery of bacterial effectors into the host cell cytoplasm allowing the bacteria to manipulate host cell cytoskeleton network as well as to interfere with intracellular signaling pathways. In this study, we investigated the potential of the Shigella flexneri T3SA as an in vivo delivery system for biologically active molecules such as cytokines. The anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist (IL-1ra) were genetically fused to the first 30 or 60 residues of the Shigella T3S effector IpaH9.8 or to the first 50 residues of the Yersinia enterocolitica effector YopE and the recombinant fusion proteins were expressed in S. flexneri. YopE50-IL-10, IpaH60-IL-10, and IpaH60-IL-1ra were efficiently secreted via the T3S apparatus of Shigella. Moreover, these recombinant proteins did not impair the invasive ability of the bacteria in vitro. In a murine model, Shigella strains expressing YopE50-IL-10, IpaH60-IL-10, and IpaH60-IL-1ra induced a lower mortality in mice that was associated with reduced inflammation and a restricted localization of bacteria within the lung tissues as compared with wild-type Shigella. Moreover, the level of TNF-α and IL-1β mRNA were reduced in the lungs following infection by IL-10- and IL-1ra-secreting Shigella, respectively. These findings demonstrate that the Shigella T3S apparatus can deliver biologically active cytokines in vivo, thus opening new avenues for the use of attenuated bacteria to deliver proteins for immunomodulation or gene therapy purposes.
Analysis of HLA-G in Maternal Plasma, Follicular Fluid, and Preimplantation Embryos Reveal an Asymmetric Pattern of Expression
Authors: Shaikly Valerie R. , Morrison Ian E. G. , Taranissi Mohamed , Noble Clare V. , Withey Anna D. , Cherry Richard J. , Blois Sandra M. , Fernández Nelson 
Published: April 2014

Abstract
Soluble HLA-G (sHLA-G) secretion by human preimplantation embryos in culture has been associated with successful embryo development, and therefore has potential to serve as a noninvasive marker of embryo viability. We have examined the spatial and temporal expression of HLA-G in embryos of varying developmental competence and the role of maternal factors in human embryonic HLA-G expression. Embryos that reached blastocyst stage on day 5 showed a higher frequency of sHLA-G secretion than those at morula or arrested stages (p &lt; 0.05). There was no significant difference in sHLA-G secretion between normal embryos and those diagnosed as chromosomally abnormal by preimplantation genetic diagnosis. HLA-G detected in maternal plasma and follicular fluid did not appear to correlate with HLA-G expressed in the embryo or embryo supernatants. Confocal microscopy analysis indicated that HLA-G protein expression in embryos was not homogeneous; mostly, it was confined to blastocysts localized on trophectoderm and trophectoderm projections. Single-particle fluorescent imaging analysis of HLA-G on the cell surface of JEG-3 cells showed that HLA-G particles were mostly monomeric, but dimeric and higher order oligomers were also observed. These results suggest that HLA-G play an important role in preimplantation embryo development. However, the observed expression of HLA-G in arrested and chromosomally abnormal embryos indicates that HLA-G testing should be used with caution and in conjunction with conventional methods of embryo screening and selection.
Modulation of Dendritic Cell Function by Leishmania Parasites
Authors: Soong Lynn 
Published: April 2014

Abstract
The interactions between Leishmania parasites and dendritic cells (DCs) are complex and involve paradoxical functions that can stimulate or halt T cell responses, leading to the control of infection or progression of disease. The magnitude and profile of DC activation vary greatly, depending upon the Leishmania species/strains, developmental stages, DC subsets, serum opsonization, and exogenous DC stimuli involved in the study. In general, the uptake of Leishmania parasites alone can trigger relatively weak and transient DC activation; however, the intracellular parasites (amastigotes) are capable of down-modulating LPS/IFN-γ-stimulated DC activation via multiple mechanisms. This review will highlight current data regarding the initial interaction of DC subsets with invading parasites, the alterations of DC signaling pathways and function by amastigotes, and the impact of DC functions on protective immunity and disease pathogenesis. Available information provides insight into the mechanisms by which DCs discriminate between the types of pathogens and regulate appropriate immune responses.
Cutting Edge: Langerin+ Dendritic Cells in the Mesenteric Lymph Node Set the Stage for Skin and Gut Immune System Cross-Talk
Authors: Chang Sun-Young , Cha Hye-Ran , Igarashi Osamu , Rennert Paul D. , Kissenpfennig Adrien , Malissen Bernard , Nanno Masanobu , Kiyono Hiroshi , Kweon Mi-Na 
Published: April 2014

AbstractTopical transcutaneous immunization (TCI) presents many clinical advantages, but its underlying mechanism remains unknown. TCI induced Ag-specific IgA Ab-secreting cells expressing CCR9 and CCR10 in the small intestine in a retinoic acid-dependent manner. These intestinal IgA Abs were maintained in Peyer’s patch-null mice but abolished in the Peyer’s patch- and lymph node-null mice. The mesenteric lymph node (MLN) was shown to be the site of IgA isotype class switching after TCI. Unexpectedly, langerin+CD8α− dendritic cells emerged in the MLN after TCI; they did not migrate from the skin but rather differentiated rapidly from bone marrow precursors. Depletion of langerin+ cells impaired intestinal IgA Ab responses after TCI. Taken together, these findings suggest that MLN is indispensable for the induction of intestinal IgA Abs following skin immunization and that cross-talk between the skin and gut immune systems might be mediated by langerin+ dendritic cells in the MLN.
Cutting Edge: Autoimmune Disease in Day 3 Thymectomized Mice Is Actively Controlled by Endogenous Disease-Specific Regulatory T Cells
Authors: Samy Eileen T. , Wheeler Karen M. , Roper Randall J. , Teuscher Cory , Tung Kenneth S. K. 
Published: April 2014

AbstractFemale B6AF1 mice thymectomized on day 3 (d3tx) develop autoimmune ovarian disease (AOD) and dacryoadenitis. It has been hypothesized that d3tx breaks tolerance by depleting late ontogeny regulatory T cells (Treg). We now report that Treg greatly expand over effector T cells in d3tx mice and adoptively suppress autoimmune disease in d3tx recipients. In the d3tx donors, Treg from ovarian lymph nodes (LN) preferentially suppress AOD and Treg from lacrimal gland LN preferentially suppress dacryoadenitis, suggesting they are strategically positioned for disease control. Indeed, the autologous disease in d3tx mice is dramatically enhanced by in vivo depletion of endogenous Treg. Moreover, normal 3-day-old mice possess Treg that suppress AOD and autoimmune gastritis as efficiently as adult cells. Thus, d3tx mice possess disease-relevant Treg of presumed neonatal origin. They accumulate in the regional LN and actively inhibit concurrent autoimmune disease; however, they cannot fully prevent autoimmune disease development.
Dendritic Cell Differentiation State and Their Interaction with NKT Cells Determine Th1/Th2 Differentiation in the Murine Model ofLeishmania majorInfection
Authors: Wiethe Carsten , Debus Andrea , Mohrs Markus , Steinkasserer Alexander , Lutz Manfred , Gessner André 
Published: April 2014

AbstractRecent reports demonstrated that dendritic cells (DC) sense inflammatory and microbial signals differently, redefining their classical subdivision into an immature endocytic and a mature Ag-presenting differentiation stage. Although both signals induce DC maturation by up-regulating MHC class II and costimulatory molecules, only TLR signals such as LPS are able to trigger proinflammatory cytokine secretion by DCs, including Th1-polarizing IL-12. Here, we explored the murine Leishmania major infection model to examine the CD4+ T cell response induced by differentially matured DCs. When partially matured TNF-DCs were injected into BALB/c mice before infection, the mice failed to control L. major infection and developed a Th2 response which was dependent on IL-4Rα signaling. In contrast, injections of fully matured LPS+CD40-DCs induced a Th1 response controlling the infection. Pulsing DCs with a lysate of L. major did not affect DC maturation with TNF-α or LPS+anti-CD40. When the expression of different Notch ligands on DCs was analyzed, we found increased expression of Th2-promoting Jagged2 in TNF-DCs, whereas LPS+CD40-DCs up-regulated the Th1-inducing Delta4 and Jagged1 molecules. The Th2 polarization induced by TNF-DCs required interaction with CD1d-restricted NKT cells. However, NKT cell activation by L. major lysate-pulsed DCs was not affected by blockade of the endogenous glycolipid, suggesting exchange with exogenous parasite-derived CD1 glycolipid Ag. In sum, the differentiation stage of DCs as well as their interaction with NKT cells determines Th1/Th2 differentiation. These results have generic implications for the understanding of DC-driven Th cell responses and the development of improved DC vaccines against leishmaniasis.
CD40 on APCs Is Needed for Optimal Programming, Maintenance, and Recall of CD8+ T Cell Memory Even in the Absence of CD4+ T Cell Help
Authors: Hernandez Maria Genevive H. , Shen Lianjun , Rock Kenneth L. 
Published: April 2014

Abstract
CD40 stimulation is one of the many signals that can activate APCs and we have recently shown it to have a unique function in generating maximum primary CD8+ T cell responses. However, whether CD40 signaling plays a role in memory CD8+ T cell responses is still not completely understood. In this study, we show that in the absence of CD40 on all APCs or specifically on dendritic cells, memory CD8+ T cells are generated but at significantly reduced levels. This reduction is due to a contribution of CD40 at several different steps in the generation of CD8+ memory. In the initial T cell response, CD40 contributes to maximizing not only the number of effector cells that are generated but also the programming of ones that will differentiate into memory. Subsequently, CD40 is needed to maintain maximal numbers of the committed memory cells in a manner that is independent of the immunizing Ag. Finally, when memory CD8+ T cells are reactivated there is a variable requirement for CD40 depending on whether CD40 or CD4+ Th cells were present during the primary response. Therefore, CD40 signaling on APCs plays an important role in all phases of a memory CD8+ T cell response.