bluuebunny/crossref_metadata_2025_split huggingface dataset:
Smad3 Null Mice Develop Airspace Enlargement and Are Resistant to TGF-β-Mediated Pulmonary Fibrosis
Authors: Bonniaud Philippe , Kolb Martin , Galt Tom , Robertson Jennifer , Robbins Clinton , Stampfli Martin , Lavery Carol , Margetts Peter J. , Roberts Anita B. , Gauldie Jack 
Published: April 2014

Abstract
Transforming growth factor-β1 plays a key role in the pathogenesis of pulmonary fibrosis, mediating extracellular matrix (ECM) gene expression through a series of intracellular signaling molecules, including Smad2 and Smad3. We show that Smad3 null mice (knockout (KO)) develop progressive age-related increases in the size of alveolar spaces, associated with high spontaneous presence of matrix metalloproteinases (MMP-9 and MMP-12) in the lung. Moreover, transient overexpression of active TGF-β1 in lungs, using adenoviral vector-mediated gene transfer, resulted in progressive pulmonary fibrosis in wild-type mice, whereas no fibrosis was seen in the lungs of Smad3 KO mice up to 28 days. Significantly higher levels of matrix components (procollagen 3A1, connective tissue growth factor) and antiproteinases (plasminogen activator inhibitor-1, tissue inhibitor of metalloproteinase-1) were detected in wild-type lungs 4 days after TGF-β1 administration, while no such changes were seen in KO lungs. These data suggest a pivotal role of the Smad3 pathway in ECM metabolism. Basal activity of the pathway is required to maintain alveolar integrity and ECM homeostasis, but excessive signaling through the pathway results in fibrosis characterized by inhibited degradation and enhanced ECM deposition. The Smad3 pathway is involved in pathogenic mechanisms mediating tissue destruction (lack of repair) and fibrogenesis (excessive repair).
Hepatic CD1d Expression in Hepatitis C Virus Infection and Recognition by Resident Proinflammatory CD1d-Reactive T Cells
Authors: Durante-Mangoni Emanuele , Wang RuoJie , Shaulov Angela , He Qi , Nasser Imad , Afdhal Nezam , Koziel Margaret J. , Exley Mark A. 
Published: April 2014

Abstract
A subset of CD161+CD56+/− NKT cells can recognize glycolipids presented by CD1d and positively or negatively regulate inflammatory responses, including those implicated in several models of hepatitis. CD1d is expressed at very low levels in the healthy liver, but there is a large fraction of CD161+CD56+ NKT cells. There are high levels of nonclassical proinflammatory hepatic CD1d-reactive T cells in hepatitis C virus (HCV) infection. Hepatic inflammatory cells and biliary cells adjacent to portal tract fibrotic areas of HCV-infected donors specifically up-regulated CD1d. A hepatocyte cell line expressing minimal CD1d was efficiently recognized by hepatic CD1d-reactive T cells, suggesting a role for these cells in disease. Hepatic CD1d-reactive T cells from HCV-positive as well as negative donors produced large amounts of IFN-γ with some IL-13, but only rarely detectable IL-4. We confirmed large numbers of hepatic CD161+ T cells, lower levels of CD56+ T cells, and small numbers of classic invariant NKT cells. However, hepatic CD1d-reactivity was not restricted to any of these populations. We suggest virally infected hepatic cells can process potent CD1d-presented liver Ag(s), for surveillance by resident Th1 hepatic CD1d-reactive T cells. This process may be beneficial in acute viral clearance, but in chronic infection could contribute to liver injury.
Monocyte Activation by Circulating Fibronectin Fragments in HIV-1-Infected Patients
Authors: Trial JoAnn , Rubio Jose A. , Birdsall Holly H. , Rodriguez-Barradas Maria , Rossen Roger D. 
Published: April 2014

Abstract
To identify signals that can alter leukocyte function in patients receiving highly active antiretroviral therapy (HAART), we analyzed single blood samples from 74 HIV-1-infected patients and additional blood was collected at 90-day intervals from 51 HIV-1-infected patients over a 516 ± 172 (mean ± SD) day interval. Despite the absence of circulating immune complexes and normalization of phagocytic function, compared with controls, the fraction of patients’ monocytes expressing CD49e and CD62L was decreased and expression of CD11b and CD86 increased. Plasma from 63% of patients but none from normal controls contained 110–120 kDa fibronectin fragments (FNf). Presence of FNf did not reflect poor adherence to therapy. Addition of FNf to normal donor blood in vitro replicated changes in monocyte CD49e, CD62L, CD11b, and CD86 seen in vivo. FNf also induced monocytes to release a serine proteinase, nominally identified as proteinase-3, that hydrolyzed cell surface CD49e. α1-Antitrypsin blocked FNf-induced shedding of CD49e in a dose-dependent manner. Plasma with a normal frequency of CD49e+ monocytes contained antiproteases that partially blocked FNf-induced monocyte CD49e shedding, whereas plasma from patients with a low frequency of CD49e+ monocytes did not block this effect of FNf. Electrophoretic analyses of plasma from the latter group of patients suggested that a significant fraction of their α1-antitrypsin was tied up in high molecular mass complexes. These results suggest that monocyte behavior in HIV-1-infected patients may be influenced by FNf and the ratio of protease and antiproteases in the cells’ microenvironment.
Preventing Intolerance: The Induction of Nonresponsiveness to Dietary and Microbial Antigens in the Intestinal Mucosa
Authors: Smith Donald W. , Nagler-Anderson Cathryn 
Published: April 2014

AbstractThe gut-associated lymphoid tissue (GALT) is constantly exposed to a variety of Ags and must therefore decipher a large number of distinct signals at all times. Responding correctly to each set of signals is crucial. When the GALT receives signals from the intestinal flora or food Ags, it must induce a state of nonresponsiveness (mucosal tolerance). In contrast, when pathogenic bacteria invade the intestinal mucosa, it is necessary to elicit strong T and B cell responses. The GALT is therefore in the position of constantly fighting intolerance to food and the commensal flora while effectively battling infectious microbes. Determining precisely which type of response to generate in each case is key to the prevention of immune dysregulation and tissue damage.
Cutting Edge: KIR2DL4 Transduces Signals into Human NK Cells through Association with the Fc Receptor γ Protein
Authors: Kikuchi-Maki Akiko , Catina Tracey L. , Campbell Kerry S. 
Published: April 2014

Abstract
KIR2DL4 (2DL4, CD158d), a member of the human killer cell Ig-like receptor (KIR) family, triggers potent IFN-γ responses but weak cytotoxicity in resting NK cells. 2DL4 mRNA has been detected in most NK cell clones from most humans examined, but surface protein expression is detectable only on CD56high NK cells from certain donors. The receptor possesses a transmembrane arginine residue, suggesting association with a signaling accessory protein that has remained elusive. We provide biochemical and functional evidence that FcεRI-γ (γ) associates with 2DL4 to promote surface expression and provide signal transducing function. Weak cytolytic responses triggered through 2DL4 may result from low stoichiometric association with γ. Selective association with γ distinguishes 2DL4 from all other activating forms of the KIR family, which alternatively associate with DNAX-activating protein (DAP)12.
Cutting Edge: IFN-γ Signaling to Macrophages Is Required for Optimal Vα14i NK T/NK Cell Cross-Talk
Authors: Wesley Johnna D. , Robbins Scott H. , Sidobre Stéphane , Kronenberg Mitchell , Terrizzi Stephanie , Brossay Laurent 
Published: April 2014

Abstract
Activated NK T cells are known to rapidly stimulate NK cells and, subsequently, CD8+ T cells and B cells. In this report, we first demonstrate that the downstream effects induced by α-galactosylceramide activated NK T cells on NK cells are mainly dependent on IFN-γ. We found that NK T cell activation of NK cells requires a functional IFN-γ signaling in macrophages and dendritic cells but not in B cells, NK cells, or NK T cells. NK T cell activation is dendritic cell-dependent whereas NK T cell activation of NK cells is indirect and in part mediated by macrophages. Interestingly, in this context, macrophage participation in the CD1d Ag presentation of α-galactosylceramide to NK T cells is not necessary. These data indicate that NK T cell-dependent activation of macrophages is required for optimal NK T cell-induced stimulation of NK cells.
Simultaneous LFA-1 and CD40 Ligand Antagonism Prevents Airway Remodeling in Orthotopic Airway Transplantation: Implications for the Role of Respiratory Epithelium as a Modulator of Fibrosis
Authors: Murakawa Tomohiro , Kerklo Michelle M. , Zamora Martin R. , Wei Yi , Gill Ronald G. , Henson Peter M. , Grover Frederick L. , Nicolls Mark R. 
Published: April 2014

Abstract
Airway remodeling is a prominent feature of certain immune-mediated lung diseases such as asthma and chronic lung transplant rejection. Under conditions of airway inflammation, the respiratory epithelium may serve an important role in this remodeling process. Given the proposed role of respiratory epithelium in nonspecific injury models, we investigated the respiratory epithelium in an immune-specific orthotopic airway transplant model. MHC-mismatched tracheal transplants in mice were used to generate alloimmune-mediated airway lesions. Attenuation of this immune injury and alteration of antidonor reactivity were achieved by the administration of combined anti-LFA-1/anti-CD40L mAbs. By contrast, without immunotherapy, transplanted airways remodeled with a flattening of respiratory epithelium and significant subepithelial fibrosis. Unopposed alloimmune injury for 10 days was associated with subsequent epithelial transformation and subepithelial fibrosis that could not be reversed with immunotherapy. The relining of donor airways with recipient-derived epithelium was delayed with immunotherapy resulting in partially chimeric airways by 28 days. Partial epithelial cell chimerism was sufficient to prevent luminal fibrosis. However, epithelial chimerism was also associated with airway remodeling. Therefore, there appears to be an intimate relationship between the morphology and level of chimerism of the respiratory epithelium and the degree of airway remodeling following alloimmune injury.
Extracellular ATP Induces Cytokine Expression and Apoptosis through P2X7 Receptor in Murine Mast Cells
Authors: Bulanova Elena , Budagian Vadim , Orinska Zane , Hein Martina , Petersen Frank , Thon Lutz , Adam Dieter , Bulfone-Paus Silvia 
Published: April 2014

AbstractExtracellular ATP and other nucleotides act through specific cell surface receptors and regulate a wide variety of cellular responses in many cell types and tissues. In this study, we demonstrate that murine mast cells express several P2Y and P2X receptor subtypes including P2X7, and describe functional responses of these cells to extracellular ATP. Stimulation of bone marrow-derived mast cells (BMMC), as well as MC/9 and P815 mast cell lines with millimolar concentrations of ATP, resulted in Ca2+ influx across the cellular membrane and cell permeabilization. Moreover, brief exposures to ATP were sufficient to induce apoptosis in BMMCs, MC/9, and P815 cells which involved activation of caspase-3 and -8. However, in the time period between commitment to apoptosis and actual cell death, ATP triggered rapid but transient phosphorylation of multiple signaling molecules in BMMCs and MC/9 cells, including ERK, Jak2, and STAT6. In addition, ATP stimulation enhanced the expression of several proinflammatory cytokines, such as IL-4, IL-6, IL-13, and TNF-α. The effects of ATP were mimicked by submillimolar concentrations of 3-O-(4′-benzoyl)-benzoyl-benzoyl-ATP, and were inhibited by pretreatment of mast cells with a selective blocker of human and mouse P2X7 receptor, 1[N,O-bis(5-isoquinolinesulphonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine, as well as oxidized ATP. The nucleotide selectivity and pharmacological profile data support the role for P2X7 receptor as the mediator of the ATP-induced responses. Given the importance of mast cells in diverse pathological conditions, the ability of extracellular ATP to induce the P2X7-mediated apoptosis in these cells may facilitate the development of new strategies to modulate mast cell activities.
IL-12 Induction of mRNA Encoding Substance P in Murine Macrophages from the Spleen and Sites of Inflammation
Authors: Arsenescu Razvan , Blum Arthur M. , Metwali Ahmed , Elliott David E. , Weinstock Joel V. 
Published: April 2014

Abstract
Substance P (SP), a neuropeptide, interacts with the neurokinin 1 receptor (NK-1R) on immune cells to help control IFN-γ production. In murine schistosomiasis mansoni, schistosome worms produce ova that incite focal Th2-type granulomatous inflammation within the liver and intestines. Normal gut is characterized by a controlled state of inflammation. IL-10 knockout mice develop chronic Th1-type colitis spontaneously. Both schistosome granulomas and gut mucosa display an SP immune regulatory circuit. However, the origin and regulation of SP production at these sites of inflammation are poorly understood. Macrophages are a potential source of SP. We therefore studied macrophages (F4/80+) from these models of inflammation. SP mRNA (preprotachykinin A (PPT A)) was detected within the schistosome granuloma, spleen, and lamina propria macrophages. Compared with those from wild-type mice, granuloma macrophages from STAT6−/− mice had 10-fold higher PPT A mRNA expression, whereas in STAT4−/− animals, PPT A mRNA expression was nearly abolished. IL-12 signals via STAT4 to induce Th1-type inflammation. It was demonstrated that IL-12, but not IL-18, induces SP mRNA expression in resting splenic macrophages from Schistosoma-infected mice and in wild-type lamina propria mononuclear cells. Thus, macrophages are a source for SP at these sites of chronic inflammation, and IL-12 and STAT4 are regulators of macrophage SP mRNA expression.
Anopheles Mosquito Bites Activate Cutaneous Mast Cells Leading to a Local Inflammatory Response and Lymph Node Hyperplasia
Authors: Demeure Christian E. , Brahimi Karima , Hacini Feriel , Marchand Françoise , Péronet Roger , Huerre Michel , St.-Mezard Pierre , Nicolas Jean-François , Brey Paul , Delespesse Guy , Mécheri Salaheddine 
Published: April 2014

Abstract
When Anopheles mosquitoes probe the skin for blood feeding, they inject saliva in dermal tissue. Mosquito saliva is known to exert various biological activities, but its perception by the immune system and its role in parasite transmission remain poorly understood. In the present study, we report on the cellular changes occurring in the mouse skin and draining lymph nodes after a Anopheles stephensi mosquito bite. We show that mosquito bites induce dermal mast cell degranulation, leading to fluid extravasation and neutrophil influx. This inflammatory response does not occur in mast cell-deficient W/Wv mice, unless these are reconstituted specifically with mast cells. Mast cell activation caused by A. stephensi mosquito bites is followed by hyperplasia of the draining lymph node due to the accumulation of CD3+, B220+, CD11b+, and CD11c+ leukocytes. The T cell enrichment of the draining lymph nodes results from their sequestration from the circulation rather than local proliferation. These data demonstrate that mosquito bites and very likely saliva rapidly trigger the immune system, emphasizing the critical contribution of peripheral mast cells in inducing T cell and dendritic cell recruitment within draining lymph nodes, a prerequisite for the elicitation of T and B lymphocyte priming.
Simultaneous Induction of CD4 T Cell Tolerance and CD8 T Cell Immunity by Semimature Dendritic Cells
Authors: Kleindienst Petra , Wiethe Carsten , Lutz Manfred B. , Brocker Thomas 
Published: April 2014

Abstract
Previous studies suggested that depending on their maturation state, dendritic cells (DC) could either induce T cell tolerance (immature and semimature DC) or T cell activation (mature DC). Pretreatment of C57BL/6 mice with encephalitogenic myelin oligodendrocyte glycoprotein (MOG)35–55 peptide-loaded semimature DC protected from MOG-induced autoimmune encephalomyelitis. This protection was mediated by IL-10-producing CD4 T cells specific for the self Ag. Here we show that semimature DC loaded with the MHC class II-restricted nonself peptide Ag (OVA) induce an identical regulatory T cell cytokine pattern. However, semimature DC loaded simultaneously with MHC class II- and MHC class I-restricted peptides, could efficiently initiate CD8 T cell responses leading to autoimmune diabetes in a TCR-transgenic adoptive transfer model. Double-peptide-loaded semimature DC also induced simultaneously in the same animal partially activated CD8 T cells with cytolytic function as well as protection from MOG-induced autoimmune encephalomyelitis. Our study suggests that the decision between tolerance and immunity not only depends on the DC, but also on the type and activation requirements of the responding T cell.
IFN Regulatory Factor-2 Cooperates with STAT1 to Regulate Transporter Associated with Antigen Processing-1 Promoter Activity
Authors: Rouyez Marie-Christine , Lestingi Marta , Charon Martine , Fichelson Serge , Buzyn Agnès , Dusanter-Fourt Isabelle 
Published: April 2014

Abstract
Class I MHC complexes (MHCI) are essential in mediating immune response. The transport of antigenic peptides (TAP) to MHCI and the stable expression of MHCI on the cell surface require the presence of a dedicated TAP. In this study we report that IFN-γ and thrombopoietin (TPO) strongly increase TAP1 protein expression in megakaryocytes, followed by an enhanced expression of MHCI on the cell surface. This expression parallels the enhanced TAP1 promoter activity and TAP1 mRNA expression, which are independent of protein synthesis. We also show that this cytokine-dependent expression of TAP1 transcripts depends on STAT1 and IFN regulatory factor-2 (IRF-2), but not on IRF-1, and provide evidence that IRF-2 constitutively binds to the TAP1 gene promoter and enhances TAP1 promoter activity. We show that IRF-2 forms a complex with STAT1 and the cytokine-responsive region of the TAP1 promoter in any TPO or IFN-γ target cells tested. Interaction of IRF-2 and STAT1 on the promoter depends on the DNA-binding domain of IRF-2. Overall, our data indicate that TPO and IFN-γ activate the expression of TAP1 via a new mechanism that involves functional cooperation between STAT1 and IRF-2 on the TAP1 promoter.
Inducing P-Selectin Ligand Formation in CD8 T Cells: IL-2 and IL-12 Are Active In Vitro but Not Required In Vivo
Authors: Carlow Douglas A. , Williams Michael J. , Ziltener Hermann J. 
Published: April 2014

Abstract
In vitro studies have demonstrated that IL-2 and IL-12 can support formation of P-selectin ligands (P-SelL) in activated T cells, ligands that are variably required for efficient lymphocyte recruitment to sites of inflammation. To ascertain whether these cytokines were required for P-SelL formation in vivo, TCR transgenic CD8 T cells specific for male Ag (HY) were transferred into male mice under conditions in which either IL-2 and/or IL-15 or IL-12Rp40 were absent. P-SelL formation at day 2 was unperturbed in HY-TCR IL-2null CD8 T cells responding in doubly deficient IL-2nullIL-12null or IL-2nullIL-15null male recipients. HY-specific CD8 T cell proliferative responses detected in both spleen and peritoneum occurred vigorously, but only splenic CD8 T cells up-regulated P-SelL, demonstrating that in vivo induction of P-SelL is an active, nonprogrammed event following T cell activation and that despite the efficacy of IL-2 and IL-12 in supporting P-SelL formation in vitro, these cytokines appear to be dispensable for this purpose in vivo.
Ex Vivo Characterization of the Autoimmune T Cell Response in the HLA-DR1 Mouse Model of Collagen-Induced Arthritis Reveals Long-Term Activation of Type II Collagen-Specific Cells and Their Presence in Arthritic Joints
Authors: Latham Kary A. , Whittington Karen B. , Zhou Ruohong , Qian Zhaohui , Rosloniec Edward F. 
Published: April 2014

Abstract
Although the pathogenesis of collagen-induced arthritis (CIA), a model of rheumatoid arthritis, is mediated by both collagen-specific CD4+ T cells and Ab specific for type II collagen (CII), the role of CII-specific T cells in the pathogenesis of CIA remains unclear. Using tetrameric HLA-DR1 with a covalently bound immunodominant CII peptide, CII259–273, we studied the development of the CII-specific T cell response in the periphery and arthritic joints of DR1 transgenic mice. Although the maximum number of DR1-CII-tetramer+ cells was detected in draining lymph nodes 10 days postimmunization, these T cells accounted for only 1% or less of the CD4+ population. After day 10, their numbers gradually decreased, but were still detectable on day 130. Examination of TCR expression and changes in CD62L, CD44high, and CD69 expression by these T cells indicated that they expressed a limited TCR-BV repertoire and had clearly undergone activation. RT-PCR analysis of cytokine expression by the tetramer+ T cells compared with tetramer− cells indicated the tetramer+ cells expressed high levels of Th1 and proinflammatory cytokines, including IL-2, IFN-γ, IL-6, TNF-α, and especially IL-17. Additionally, analysis of the synovium from arthritic paws indicated that the same CD4+/BV8+/BV14+/tetramer+ T cells were present in the arthritic joints. These data demonstrate that although only small numbers of CII-specific T cells are generated during the development of CIA, these cells express very high levels of cytokine mRNA and appear to preferentially migrate to the arthritic joint, indicating a potential direct role of CII-specific T cells in the pathogenesis of CIA.
Effector CD4+ T Cells Generate Intermediate Caspase Activity and Cleavage of Caspase-8 Substrates
Authors: Misra Ravi S. , Jelley-Gibbs Dawn M. , Russell Jennifer Q. , Huston Gail , Swain Susan L. , Budd Ralph C. 
Published: April 2014

Abstract
Caspase-8 activation promotes cell apoptosis but is also essential for T cell activation. The extent of caspase activation and substrate cleavage in these divergent processes remains unclear. We show that murine effector CD4+ T cells generated levels of caspase activity intermediate between unstimulated T cells and apoptotic populations. Both caspase-8 and caspase-3 were partially activated in effector T cells, which was reflected in cleavage of the caspase-8 substrates, c-FLIPL, receptor interacting protein 1, and to a lesser extent Bid, but not the caspase-3 substrate inhibitor of caspase-activated DNase. Th2 effector CD4+ T cells manifested more caspase activity than did Th1 effectors, and caspase blockade greatly decreased initiation of cell cycling. The current findings define the level of caspase activity and substrates during initiation of T cell cycling.