bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polarized Uterine Epithelial Cells Preferentially Present Antigen at the Basolateral Surface: Role of Stromal Cells in Regulating Class II-Mediated Epithelial Cell Antigen Presentation
Authors: Wira Charles R. , Rossoll Richard M. , Young Roger C. 
Published: April 2014

Abstract
To study Ag presentation in the female reproductive tract, DO11.10 TCR transgenic mice specific for the class II MHC-restricted OVA323–339 peptide and nontransgenic BALB/c mice were used. We report here that freshly isolated uterine epithelial cells, uterine stromal, and vaginal APCs present OVA and OVA323–339peptide to naive- and memory T cells, which is reduced when cells are incubated with Abs to CD80 and 86. To determine whether polarized primary epithelial cells present Ags, uterine epithelial cells were cultured on cell inserts in either the upright or inverted position. After reaching confluence, as indicated by high transepithelial resistance (&gt;2000 ohms/well), Ag presentation by epithelial cells incubated with memory T cells and OVA323–339 peptide placed on the basolateral surface (inverted) was 2- to 3-fold greater than that seen with epithelial cells in contact with T cells and peptide on the apical surface (upright). In contrast, whereas freshly isolated epithelial cells process OVA, polarized epithelial cells did not. When epithelial cells grown upright on inserts were incubated with T cells and OVA323–339 peptide, coculture with either hepatocyte growth factor or conditioned stromal medium increased epithelial cell Ag presentation (∼90% higher than controls). These studies indicate that uterine stromal cells produce a soluble factor(s) in addition to a hepatocyte growth factor, which regulates epithelial cell Ag presentation. Overall, these results demonstrate that polarized epithelial cells are able to present Ags and suggest that uterine stromal cells communicate with epithelial cells via a soluble factor(s) to regulate Ag presentation in the uterus.
CD43 Is Required for Optimal Growth Inhibition of Mycobacterium tuberculosis in Macrophages and in Mice
Authors: Randhawa April K. , Ziltener Hermann J. , Merzaban Jasmeen S. , Stokes Richard W. 
Published: April 2014

Abstract
We explored the role of macrophage (Mφ) CD43, a transmembrane glycoprotein, in the pathogenesis of Mycobacterium tuberculosis. Using gene-deleted mice (CD43−/−), we assessed the association of the bacterium with distinct populations of Mφ and found that CD43−/− Mφ bound less M. tuberculosis than CD43+/+ Mφ. Increased infective doses did not abrogate this difference. However, reduced association due to the absence of CD43 could be overcome by serum components. Mφ from heterozygote mice, which express 50% of wild-type CD43, bound more bacteria than CD43−/− but less than CD43+/+, proving that the gene dose of CD43 correlates with binding of M. tuberculosis. Furthermore, the reduced ability of CD43−/− Mφ to bind bacteria was restricted to mycobacterial species. We also found that the survival and replication of M. tuberculosis within Mφ was enhanced significantly in the absence of CD43, making this the first demonstration that the mechanism of mycobacterial entry influences its subsequent growth. Most importantly, we show here that the absence of CD43 in mice aerogenically infected with M. tuberculosis results in an increased bacterial load during both the acute and chronic stages of infection and more rapid development of granulomas, with greater lung involvement and distinctive cellularity.
Depletion of T Cells by Type I Interferon: Differences between Young and Aged Mice
Authors: Jiang Jiu , Gross Diara , Nogusa Shoko , Elbaum Philip , Murasko Donna M. 
Published: April 2014

Abstract
Type I IFN (IFN-I or IFN-αβ) plays an important role in the innate immune response against viral infection. Here we report that a potent inducer of IFN-αβ, polyinosinic-polycytidylic acid [poly(I:C)], led to the depletion of T cells in young, but not aged mice, and that this depletion was limited to central memory, but not effector memory, T cells. Although early activation of T cells in vivo by poly(I:C), as demonstrated by CD69, was not impaired with aging, the expression of active caspase-3 was higher in young compared with aged mice. This depletion of T cells and induction of active caspase-3 in young mice and of CD69 in both young and aged mice by poly(I:C) were blocked by anti-IFN-αβ Ab. Although poly(I:C) stimulated lower circulating levels of IFN-αβ in aged mice, administration of IFN-αβ after poly(I:C) did not induce depletion of T cells in aged mice. These results indicate that IFN-αβ plays a critical role in the depletion of T cells of young mice, and further suggest that the lower level of functional IFN-αβ and decreased induction of active caspase-3 in T cells of aged mice after poly(I:C) may be responsible for the increased resistance of T cells of aged mice to depletion.
Involvement of the Rho-Kinase/Myosin Light Chain Kinase Pathway on Human Monocyte Chemotaxis Induced by ATL-1, an Aspirin-Triggered Lipoxin A4 Synthetic Analog
Authors: Simões Rafael L. , Fierro Iolanda M. 
Published: April 2014

AbstractLipoxins (LX) are arachidonic acid metabolites able to induce monocyte chemotaxis in vitro and in vivo. Nonetheless, the signaling pathways mediating this process are yet unclear. In this study, we have investigated the mechanisms associated with human monocyte activation in response to 15-epi-16-(para-fluoro)-phenoxy-LXA4 (ATL-1), a stable 15-epi-LXA4 analog. Our results demonstrate that ATL-1-induced monocyte chemotaxis (10–300 nM) is inhibited by pertussis toxin, suggesting an effect via the G-protein-linked LXA4 receptor. Monocytes stimulated with the analog presented an increased ERK-2 phosphorylation, which was reduced by PD98059, a selective inhibitor of the MEK 1/2 pathway. After exposure of the cells to ATL-1, myosin L chain kinase (MLCK) phosphorylation was evident and this effect was inhibited by PD98059 or Y-27632, a specific inhibitor of Rho kinase. In addition, Y-27632 abolished ERK-2 activation, suggesting that the MAPK pathway is downstream of Rho/Rho kinase in MLCK activation induced by ATL-1. The specific MLCK inhibitor ML-7, as well as Y-27632, abrogated monocyte chemotaxis stimulated by the analog, confirming the central role of the Rho kinase/MLCK pathway on ATL-1 action. Together, these results indicate that ATL-1 acts as a potent monocyte chemoattractant via Rho kinase and MLCK. The present study clarifies some of the mechanisms involved on the activation of monocytes by LXs and opens new avenues for investigation of these checkpoint controllers of inflammation.
Lyn-Deficient Mice Develop Severe, Persistent Asthma: Lyn Is a Critical Negative Regulator of Th2 Immunity
Authors: Beavitt Sarah-Jane E. , Harder Kenneth W. , Kemp Joanna M. , Jones Jessica , Quilici Cathy , Casagranda Franca , Lam Ellen , Turner Debra , Brennan Siobhain , Sly Peter D. , Tarlinton David M. , Anderson Gary P. , Hibbs Margaret L. 
Published: April 2014

Abstract
The etiology of asthma, a chronic inflammatory disorder of the airways, remains obscure, although T cells appear to be central disease mediators. Lyn tyrosine kinase has been implicated as both a facilitator and inhibitor of signaling pathways that play a role in allergic inflammation, although its role in asthma is unclear because Lyn is not expressed in T cells. We show in the present study that Lyn−/− mice develop a severe, persistent inflammatory asthma-like syndrome with lung eosinophilia, mast cell hyperdegranulation, intensified bronchospasm, hyper IgE, and Th2-polarizing dendritic cells. Dendritic cells from Lyn−/− mice have a more immature phenotype, exhibit defective inhibitory signaling pathways, produce less IL-12, and can transfer disease when adoptively transferred into wild-type recipients. Our results show that Lyn regulates the intensity and duration of multiple asthmatic traits and indicate that Lyn is an important negative regulator of Th2 immune responses.
The Inflammatory versus Constitutive Trafficking of Mononuclear Phagocytes into the Alveolar Space of Mice Is Associated with Drastic Changes in Their Gene Expression Profiles
Authors: Srivastava Mrigank , Jung Steffen , Wilhelm Jochen , Fink Ludger , Bühling Frank , Welte Tobias , Bohle Rainer M. , Seeger Werner , Lohmeyer Jürgen , Maus Ulrich A. 
Published: April 2014

Abstract
Mononuclear phagocytes enter the lungs both constitutively to maintain alveolar macrophage and dendritic cell homeostasis, as well as during lung inflammation, where the role of these cells is less well defined. We used a transgenic mouse strain (CX3CR1+/GFP) that harbors a GFP label in circulating monocytes to identify and sort these cells from the vascular and alveolar compartments under both constitutive and acute lung inflammatory conditions. Using nylon arrays combined with real-time RT-PCR for gene expression profiling, we found that flow-sorted, highly purified mononuclear phagocytes recruited to acutely inflamed mouse lungs showed strongly up-regulated mRNA levels of the neutrophil chemoattractants KC, MIP-2, and IP-10, which contrasted with alveolar mononuclear phagocytes that immigrated in steady state. Similar observations were made for the lysosomal cathepsins B, L, and K being strongly up-regulated in mononuclear phagocytes upon recruitment to inflamed lungs but not during constitutive alveolar immigration. Inflammatory elicited mononuclear phagocytes also demonstrated significantly increased mRNA levels of the cytokine TNF-α and the PRR-associated molecules CD14, TLR4, and syndecan-4. Together, inflammatory elicited mononuclear phagocytes exhibit strongly increased neutrophil chemoattractants, lysosomal proteases, and LPS signaling mRNA transcripts, suggesting that these cells may play a major role in acute lung inflammatory processes.
Opposing Regulatory Roles of Complement Factor 5 in the Development of Bleomycin-Induced Pulmonary Fibrosis
Authors: Addis-Lieser Erin , Köhl Jörg , Chiaramonte Mónica G. 
Published: April 2014

Abstract
The mechanisms of idiopathic pulmonary fibrosis pathogenesis, a chronic and progressive interstitial lung disease, remain elusive. The complement system, a crucial arm of the innate immune response, plays a pivotal role in several pathological disorders; however, the contribution of individual complement components to lung fibrosis has not yet been examined. Complement factor 5 (C5) and its cleavage product C5a are critical mediators in inflammatory diseases. Thus, to evaluate the role of C5 in lung fibrosis, we compared congenic C5-sufficient and C5-deficient mice in a well-characterized murine model of bleomycin-induced pulmonary fibrosis. C5-deficient mice had an exaggerated inflammatory phenotype compared with C5-sufficient mice during acute bleomycin-induced lung injury. These findings suggest a protective and anti-inflammatory role for C5, which was linked to the regulation of matrix metalloproteinases involved in cell migration. In contrast, C5 had a detrimental effect during chronic stages of bleomycin-induced injury, indicating a profibrotic role for C5. This deleterious activity for C5 was associated with expression of the fibrogenic cytokine TGF-β1 and matrix metalloproteinase-3, an important mediator in fibroblast contraction. Altogether, our data reveal novel and opposing roles for C5 in both inflammation and tissue repair. Furthermore, these findings provide insight into the development of new therapeutic strategies for idiopathic pulmonary fibrosis patients.
Bacterial Induction of TNF-α Converting Enzyme Expression and IL-6 Receptor α Shedding Regulates Airway Inflammatory Signaling
Authors: Gómez Marisa I. , Sokol Sach H. , Muir Amanda B. , Soong Grace , Bastien Jayson , Prince Alice S. 
Published: April 2014

Abstract
Airway epithelial cells have a major role in initiating inflammation in response to bacterial pathogens. Through the immediate induction of CXCL8 and cytokine expression, polymorphonuclear cells are mobilized and activated to eradicate the infecting organisms. However, the influx of polymorphonuclear cells and the effects of their toxic exoproducts impede respiratory function. We postulated that respiratory epithelial cells must also participate in the regulation of their own proinflammatory signaling. Both Staphylococcus aureus and Pseudomonas aeruginosa were found to potently activate IL-6 expression immediately upon contact with epithelial cells, and by 1 h induced TNF-α converting enzyme (TACE) transcription. By 4 h of bacterial exposure, TACE colocalized with IL-6Rα on the apical surface of airway cells, and by 24 h, soluble IL-6Rα accumulated in the cell culture supernatant. Epithelial IL-6 and soluble IL-6Rα were shown to participate in trans-signaling, interacting with membrane-associated gp130 to activate CCL-2 expression and inhibit additional CXCL8 production. Thus, bacteria are physiological activators of TACE expression, which provides a mechanism to regulate inflammatory signaling that is initiated by airway epithelial cells.
Signaling through Up-Regulated C3a Receptor Is Key to the Development of Experimental Lupus Nephritis
Authors: Bao Lihua , Osawe Iyabo , Haas Mark , Quigg Richard J. 
Published: April 2014

AbstractSignaling of the C3a anaphylatoxin through its G protein-coupled receptor, C3aR, is relevant in a variety of inflammatory diseases, but its role in lupus nephritis is undefined. In this study, we show that expression of C3aR was significantly increased in prediseased and diseased kidneys of MRL/lpr lupus mice compared with MRL/+ controls. To investigate the role of C3aR in experimental lupus, a small molecule antagonist of C3aR (C3aRa) was administered continuously to MRL/lpr mice from 13 to 19 wk of age. All 13 C3aRa-treated mice survived during the 6-wk treatment compared with 9 of 14 (64.3%) control animals given vehicle (p = 0.019). Relative to controls, C3aRa-treated animals were protected from renal disease as measured by albuminuria (p = 0.040) and blood urea nitrogen (p = 0.021). In addition, there were fewer neutrophils, monocytes, and apoptotic cells in the kidneys of C3aRa-treated mice. C3aRa treatment also led to reduced renal IL-1β and RANTES mRNA and phosphorylated phosphatase and tensin homologue deleted on chromosome 10 protein, whereas the mass of phosphorylated protein kinase B/Akt was increased by C3aRa. Thus, C3aR antagonism significantly reduces renal disease in MRL/lpr mice, which further translates into prolonged survival. These data illustrate that C3aR is relevant in experimental lupus nephritis and may be a target for therapeutic intervention in the human disease.
The Role of Fas in the Immune System Biology of IL-2Rα Knockout Mice: Interplay among Regulatory T Cells, Inflammation, Hemopoiesis, and Apoptosis
Authors: Sharma Rahul , Bagavant Harini , Jarjour Wael N. , Sung Sun-Sang J. , Ju Shyr-Te 
Published: April 2014

Abstract
Introducing lpr mutation prevents early mortality associated with IL-2Rα knockout (KO) mice, prompting us to determine the role of Fas in the immune system biology of IL-2Rα KO mice. Consistent with a defect in CD4+CD25+ regulatory T (Treg) cell expression, spontaneous lymphocyte activation in lymphoid organs was observed in 6-wk-old mice. In 16- to 22-wk-old mice, infiltration of leukocytes was observed in bone marrow, colon, lung, pancreas, lacrimal gland, and salivary gland, but not in heart, thyroid, liver, stomach, small intestine, ovary, and kidney. In the lymphocytes-infiltrated bone marrow, B cell lymphopoiesis was blocked at pro-B to pre-B/immature B stage, culminating in an age-dependent B cell loss in the periphery. These phenotypes were also observed in IL-2Rα KO mice bearing the lpr mutation (DM mice), indicating Treg cell function and the phenotypes attributed directly to Treg cell abnormality are largely Fas-independent. However, anemia and body weight loss were partially prevented, tissue cell apoptosis was inhibited, and lifespan was improved in the DM mice, demonstrating Fas-dependent elements in these processes. Our age-dependent, lifelong analysis of IL-2Rα KO and DM mice supports a CD4+CD25+ Treg cell-based mechanism for the abnormal immune system biology observed in IL-2Rα KO mice and provides a global view of the interplays among Treg cells, multiorgan inflammation, hemopoiesis, and apoptosis.
Reconstitution of EBV Latent but Not Lytic Antigen-Specific CD4+ and CD8+ T Cells after HIV Treatment with Highly Active Antiretroviral Therapy
Authors: Piriou Erwan , Jansen Christine A. , Dort Karel van , De Cuyper Iris , Nanlohy Nening M. , Lange Joep M. A. , van Oers Marinus H. J. , Miedema Frank , van Baarle Debbie 
Published: April 2014

Abstract
The incidence of (EBV-related) malignancies in HIV-infected subjects has declined since the introduction of highly active antiretroviral therapy (HAART). To investigate the effect of HAART on EBV infection, we performed a longitudinal analysis of the T cell response to both a latent and a lytic Ag and EBV viral load in 10 subjects from early in HIV infection up to 5 years after HAART. All individuals responded to HAART by a decline in HIV viral load, a restoration of total CD4+ T cell numbers, and a decline in T cell immune activation. Despite this, EBV load remained unaltered, even after 5 years of therapy, although a decline in both CD4+ and CD8+ T cells specific for the lytic EBV protein BZLF1 suggested a decreased EBV reactivation rate. In contrast, latent EBV Ag EBNA1-specific CD4+ and CD8+ T cell responses were restored after 5 years of treatment to levels comparable to healthy individuals. In two individuals who were treated by HAART late during HIV progression, a lymphoma developed shortly after initiation of HAART, despite restoration of EBV-specific CD4+ and CD8+ T cells. In conclusion, long-term HAART does not alter the EBV DNA load, but does lead to a restoration of EBNA1-specific T cell responses, which might allow better control of EBV-infected cells when applied early enough during HIV infection.
IL-1 Receptor Antagonist-Mediated Therapeutic Effect in Murine Myasthenia Gravis Is Associated with Suppressed Serum Proinflammatory Cytokines, C3, and Anti-Acetylcholine Receptor IgG1
Authors: Yang Huan , Tüzün Erdem , Alagappan Dhivyaa , Yu Xiang , Scott Benjamin G. , Ischenko Alexander , Christadoss Premkumar 
Published: April 2014

AbstractIn myasthenia gravis (MG), TNF and IL-1β polymorphisms and high serum levels of these proinflammatory cytokines have been observed. Likewise, TNF and IL-1β are critical for the activation of acetylcholine receptor (AChR)-specific T and B cells and for the development of experimental autoimmune myasthenia gravis (EAMG) induced by AChR immunization. We tested the therapeutic effect of human recombinant IL-1 receptor antagonist (IL-1ra) in C57BL/6 mice with EAMG. Multiple daily injections of 0.01 mg of IL-1ra administered for 2 wk following two AChR immunizations decreased the incidence and severity of clinical EAMG. Furthermore, IL-1ra treatment of mice with ongoing clinical EAMG reduced the clinical symptoms of disease. The IL-1ra-mediated suppression of clinical disease was associated with suppressed serum IFN-γ, TNF-α, IL-1β, IL-2, IL-6, C3, and anti-AChR IgG1 without influencing total serum IgG. Therefore, IL-1ra could be used as a nonsteroidal drug for the treatment of MG.
Cutting Edge: Critical Role of CXCL16/CXCR6 in NKT Cell Trafficking in Allograft Tolerance
Authors: Jiang Xiaofeng , Shimaoka Takeshi , Kojo Satoshi , Harada Michishige , Watarai Hiroshi , Wakao Hiroshi , Ohkohchi Nobuhiro , Yonehara Shin , Taniguchi Masaru , Seino Ken-ichiro 
Published: April 2014

Abstract
It is well-documented that certain chemokines or their receptors play important roles in the graft rejection. However, the roles of chemokines and their receptors in the maintenance of transplantation tolerance remain unclear. In this study, we demonstrate that blocking of the interaction between the chemokine receptor, CXCR6, highly expressed on Vα14+ NKT cells and its ligand, CXCL16, resulted in the failure to maintain graft tolerance and thus in the induction of acceleration of graft rejection. In a mouse transplant tolerance model, the expression of CXCL16 was up-regulated in the tolerated allografts, and anti-CXCL16 mAb inhibited intragraft accumulation of NKT cells. In vitro experiments further showed that blocking of CXCL16/CXCR6 interaction significantly affected not only chemotaxis but also cell adhesion of NKT cells. These results demonstrate the unique role of CXCL16 and CXCR6 molecules in the maintenance of cardiac allograft tolerance mediated by NKT cells.
Cutting Edge: Polymorphisms in the ICOS Promoter Region Are Associated with Allergic Sensitization and Th2 Cytokine Production
Authors: Shilling Rebecca A. , Pinto Jayant M. , Decker Donna C. , Schneider Daniel H. , Bandukwala Hozefa S. , Schneider Jeffrey R. , Camoretti-Mercado Blanca , Ober Carole , Sperling Anne I. 
Published: April 2014

Abstract
The establishment of ICOS as an important regulator of Th2 development and effector function makes the ICOS locus an attractive candidate for Th2-mediated diseases, such as asthma and allergy. In evaluation of this candidate locus in humans, we identified 11 variants and determined that two in the putative promoter region are significantly associated with allergic sensitization and serum IgE levels. In addition, cultures of activated PBMCs from individuals homozygous for the associated polymorphisms produced increased levels of the Th2 cytokines, IL-4, IL-5, and IL-13, as well as TNF-α compared with controls. One of the polymorphisms, −1413G/A, demonstrated differential NF-κB binding in mobility shift analysis, suggesting that this polymorphism has functional consequences. Overall, these data demonstrate that ICOS is a susceptibility gene for allergic sensitization, perhaps through the promotion of Th2 differentiation.
Activation of Vγ9Vδ2 T Cells by NKG2D
Authors: Rincon-Orozco Bladimiro , Kunzmann Volker , Wrobel Philine , Kabelitz Dieter , Steinle Alexander , Herrmann Thomas 
Published: April 2014

Abstract
Human Vγ9Vδ2 T cells recognize phosphorylated nonpeptide Ags (so called phosphoantigens), certain tumor cells, and cells treated with aminobisphosphonates. NKG2D, an activating receptor for NK cells, has been described as a potent costimulatory receptor in the Ag-specific activation of γδ and CD8 T cells. This study provides evidence that Vγ9Vδ2 T cells may also be directly activated by NKG2D. Culture of PBMC with immobilized NKG2D-specific mAb or NKG2D ligand MHC class I related protein A (MICA) induces the up-regulation of CD69 and CD25 in NK and Vγ9Vδ2 but not in CD8 T cells. Furthermore, NKG2D triggers the production of TNF-α but not of IFN-γ, as well as the release of cytolytic granules by Vγ9Vδ2 T cells. Purified Vγ9Vδ2 T cells kill MICA-transfected RMA mouse cells but not control cells. Finally, DAP10, which mediates NKG2D signaling in human NK cells, was detected in resting and activated Vγ9Vδ2 T cells. These remarkable similarities in NKG2D function in NK and Vγ9Vδ2 T cells may open new perspectives for Vγ9Vδ2 T cell-based immunotherapy, e.g., by Ag-independent killing of NKG2D ligand-expressing tumors.