bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancer-Mediated Control of Macrophage-Specific Arginase I Expression
Authors: Pauleau Anne-Laure , Rutschman Robert , Lang Roland , Pernis Alessandra , Watowich Stephanie S. , Murray Peter J. 
Published: April 2014

AbstractArginase I expression in the liver must remain constant throughout life to eliminate excess nitrogen via the urea cycle. In contrast, arginase I expression in macrophages is silent until signals from Th2 cytokines such as IL-4 and IL-13 are received and the mRNA is then induced four to five orders of magnitude. Arginase I is hypothesized to play a regulatory and potentially pathogenic role in diseases such as asthma, parasitic, bacterial, and worm infections by modulating NO levels and promoting fibrosis. We show that Th2-inducible arginase I expression in mouse macrophages is controlled by an enhancer that lies −3 kb from the basal promoter. PU.1, IL-4-induced STAT6, and C/EBPβ assemble at the enhancer and await the effect of another STAT6-regulated protein(s) that must be synthesized de novo. Identification of a powerful extrahepatic regulatory enhancer for arginase I provides potential to manipulate arginase I activity in immune cells while sparing liver urea cycle function.
Pulmonary Collectins Enhance Phagocytosis of Mycobacterium avium through Increased Activity of Mannose Receptor
Authors: Kudo Kazumi , Sano Hitomi , Takahashi Hiroki , Kuronuma Koji , Yokota Shin-ichi , Fujii Nobuhiro , Shimada Ken-ichi , Yano Ikuya , Kumazawa Yoshio , Voelker Dennis R. , Abe Shosaku , Kuroki Yoshio 
Published: April 2014

Abstract
Collectins, including surfactant proteins A (SP-A) and D (SP-D) and mannose binding lectin (MBL), are the important constituents of the innate immune system. Mycobacterium avium, a facultative intracellular pathogen, has developed numerous mechanisms for entering mononuclear phagocytes. In this study, we investigated the interactions of collectins with M. avium and the effects of these lectins on phagocytosis of M. avium by macrophages. SP-A, SP-D, and MBL exhibited a concentration-dependent binding to M. avium. The binding of SP-A to M. avium was Ca2+-dependent but that of SP-D and MBL was Ca2+-independent. SP-A and SP-D but not MBL enhanced the phagocytosis of FITC-labeled M. avium by rat alveolar macrophages and human monocyte-derived macrophages. Excess mannan, zymosan, and lipoarabinomannan derived from the M. avium-intracellular complex, significantly decreased the collectin-stimulated phagocytosis of M. avium. Enhanced phagocytosis was not affected by the presence of cycloheximide or chelation of Ca2+. The mutated collectin, SP-AE195Q, R197D exhibited decreased binding to M. avium but stimulated phagocytosis to a level comparable to wild-type SP-A. Enhanced phagocytosis by cells persisted even after preincubation and removal of SP-A or SP-D. Rat alveolar macrophages that had been incubated with SP-A or SP-D also exhibited enhanced uptake of 125I-mannosylated BSA. Analysis by confocal microscopy and flow cytometry revealed that the lung collectins up-regulated the cell surface expression of mannose receptor on monocyte-derived macrophages. These results provide compelling evidence that SP-A and SP-D enhance mannose receptor-mediated phagocytosis of M. avium by macrophages.
IL-10 Is an Important Mediator of the Enhanced Susceptibility to Pneumococcal Pneumonia after Influenza Infection
Authors: van der Sluijs Koenraad F. , van Elden Leontine J. R. , Nijhuis Monique , Schuurman Rob , Pater Jennie M. , Florquin Sandrine , Goldman Michel , Jansen Henk M. , Lutter René , van der Poll Tom 
Published: April 2014

Abstract
Secondary pneumococcal pneumonia is a serious complication during and shortly after influenza infection. We established a mouse model to study postinfluenza pneumococcal pneumonia and evaluated the role of IL-10 in host defense against Streptococcus pneumoniae after recovery from influenza infection. C57BL/6 mice were intranasally inoculated with 10 median tissue culture infective doses of influenza A (A/PR/8/34) or PBS (control) on day 0. By day 14 mice had regained their normal body weight and had cleared influenza virus from the lungs, as determined by real-time quantitative PCR. On day 14 after viral infection, mice received 104 CFU of S. pneumoniae (serotype 3) intranasally. Mice recovered from influenza infection were highly susceptible to subsequent pneumococcal pneumonia, as reflected by a 100% lethality on day 3 after bacterial infection, whereas control mice showed 17% lethality on day 3 and 83% lethality on day 6 after pneumococcal infection. Furthermore, 1000-fold higher bacterial counts at 48 h after infection with S. pneumoniae and, particularly, 50-fold higher pulmonary levels of IL-10 were observed in influenza-recovered mice than in control mice. Treatment with an anti-IL-10 mAb 1 h before bacterial inoculation resulted in reduced bacterial outgrowth and markedly reduced lethality during secondary bacterial pneumonia compared with those in IgG1 control mice. In conclusion, mild self-limiting influenza A infection renders normal immunocompetent mice highly susceptible to pneumococcal pneumonia. This increased susceptibility to secondary bacterial pneumonia is at least in part caused by excessive IL-10 production and reduced neutrophil function in the lungs.
Accumulation of γδ T Cells in the Lungs and Their Regulatory Roles in Th1 Response and Host Defense against Pulmonary Infection with Cryptococcus neoformans
Authors: Uezu Kaori , Kawakami Kazuyoshi , Miyagi Kazuya , Kinjo Yuki , Kinjo Takeshi , Ishikawa Hiromichi , Saito Atsushi 
Published: April 2014

Abstract
The present study was designed to elucidate the role of γδ T cells in the host defense against pulmonary infection with Cryptococcus neoformans. The γδ T cells in lungs commenced to increase on day 1, reached a peak level on day 3 or 6, and then decreased on day 10 after intratracheal infection. The increase of these cells was similar in monocyte chemoattractant protein (MCP)-1-deficient mice, although that of NK and NKT cells was significantly reduced. The number of live microorganisms in lungs on days 14 and 21 was significantly reduced in mice depleted of γδ T cells by a specific mAb compared with mice treated with control IgG. Similarly, elimination of this fungal pathogen was promoted in γδ T cell-deficient (TCR-δ−/−) mice compared with control littermate mice. Finally, lung and serum levels of IFN-γ on days 7 and 14 and on day 7 postinfection, respectively, were significantly higher in TCR-δ−/− mice than in littermate mice, whereas levels of TGF-β showed the opposite results. IL-4 and IL-10 were not different between these mice. IFN-γ production by draining lymph node cells upon restimulation with cryptococcal Ags was significantly higher in the infected TCR-δ−/− mice than in control mice. Our results demonstrated that γδ T cells accumulated in the lungs in a manner different from NK and NKT cells after cryptococcal infection and played a down-modulatory role in the development of Th1 response and host resistance against this fungal pathogen.
Differential Regulation of TNF-R1 Signaling: Lipid Raft Dependency of p42mapk/erk2 Activation, but Not NF-κB Activation
Authors: Doan Joyce E. S. , Windmiller David A. , Riches David W. H. 
Published: April 2014

AbstractThe TNFR, TNF-R1, is localized to lipid raft and nonraft regions of the plasma membrane. Ligand binding sets in motion signaling cascades that promote the activation of p42mapk/erk2 and NF-κB. However, the role of receptor localization in the activation of downstream signaling events is poorly understood. In this study, we investigated the dynamics of TNF-R1 localization to lipid rafts and the consequences of raft localization on the activation of p42mapk/erk2 and NF-κB in primary cultures of mouse macrophages. Using sucrose density gradient ultracentrifugation and a sensitive ELISA to detect TNF-R1, we show that TNF-R1 is rapidly and transiently recruited to lipid rafts in response to TNF-α. Disruption of lipid rafts by cholesterol depletion prevented the TNF-α-dependent recruitment of TNF-R1 to lipid rafts and inhibited the activation of p42mapk/erk2, while the activation of NF-κB was unaffected. In addition, phosphorylated p42mapk/erk2, but not receptor interacting protein, I-κB kinase-γ, or I-κBα was detected in raft-containing fractions following TNF-α stimulation. These findings suggest that TNF-R1 is localized to both lipid raft and nonraft regions of the plasma membrane and that each compartment is capable of initiating different signaling responses. We propose that segregation of TNF-R1 to raft and nonraft regions of the plasma membrane contributes to the diversity of signaling responses initiated by TNF-R1.
An Annexin 1 N-Terminal Peptide Activates Leukocytes by Triggering Different Members of the Formyl Peptide Receptor Family
Authors: Ernst Stefanie , Lange Carsten , Wilbers Andreas , Goebeler Verena , Gerke Volker , Rescher Ursula 
Published: April 2014

Abstract
The human N-formyl peptide receptor (FPR) is a key modulator of chemotaxis directing granulocytes toward sites of bacterial infections. FPR is the founding member of a subfamily of G protein-coupled receptors thought to function in inflammatory processes. The other two members, FPR-like (FPRL)1 and FPRL2, have a greatly reduced affinity for bacterial peptides or do not bind them at all, with FPRL2 being considered an orphan receptor so far. In this study we show that a peptide derived from the N-terminal domain of the anti-inflammatory protein annexin 1 (lipocortin 1) can activate all three FPR family members at similar concentrations. The annexin 1 peptide initiates chemotactic responses in human monocytes that express all three FPR family members and also desensitizes the cells toward subsequent stimulation with bacterial peptide agonists. Experiments using HEK 293 cells stably expressing a single FPR family member reveal that all three receptors can be activated and desensitized by the N-terminal annexin 1 peptide. These observations identify the annexin 1 peptide as the first endogenous ligand of FPRL2 and indicate that annexin 1 participates in regulating leukocyte emigration into inflamed tissue by activating and desensitizing different receptors of the FPR family.
15-Deoxy-Δ12,14-Prostaglandin J2 Inhibits Glucocorticoid Binding and Signaling in Macrophages through a Peroxisome Proliferator-Activated Receptor γ-Independent Process
Authors: Cheron Adeline , Peltier Julie , Perez Joëlle , Bellocq Agnès , Fouqueray Bruno , Baud Laurent 
Published: April 2014

Abstract
15-Deoxy-Δ12,14-PGJ2 (15d-PGJ2) is involved in the control of inflammatory reaction. We tested the hypothesis that 15d-PGJ2 would exert this control in part by modulating the sensitivity of inflammatory cells to glucocorticoids. Human U937cells and mouse RAW 264.7 cells were exposed to 15d-PGJ2, and binding experiments were performed with [3H]dexamethasone as a glucocorticoid receptor (GR) ligand. 15d-PGJ2 caused a transient and concentration-dependent decrease in [3H]dexamethasone-specific binding to either cells through a decrease in the number of GR per cell without significant modification of the Kd value. These changes were related to functional alteration of the GR rather than to a decrease in GR protein. They did not require the engagement of peroxisome proliferator-activated receptor γ (PPARγ), because the response to 15d-PGJ2 was neither mimicked by the PPARγ agonist ciglitazone nor prevented by the PPARγ antagonist bisphenol A diglycidyl ether. 15d-PGJ2 altered GR possibly through the interaction of its cyclopentenone ring with GR cysteine residues because the cyclopentenone ring per se could mimic the effect of 15d-PGJ2, and modification of GR cysteine residues with methyl methanethiosulfonate suppressed the response to 15d-PGJ2. Finally, 15d-PGJ2-induced decreases in glucocorticoid binding to GR resulted in parallel decreases in the ability of GR to activate the transcription of a glucocorticoid-inducible reporter gene and to reduce the expression of monocyte chemoattractant protein-1. Together these data suggest that 15d-PGJ2 limits glucocorticoid binding and signaling in monocytes/macrophages through a PPARγ-independent and cyclopentenone-dependent mechanism. It provides a way in which 15d-PGJ2 would exert proinflammatory activities in addition to its known anti-inflammatory activities.
Staging the Initiation of Autoantibody-Induced Arthritis: A Critical Role for Immune Complexes
Authors: Wipke Brian T. , Wang Zheng , Nagengast Wouter , Reichert David E. , Allen Paul M. 
Published: April 2014

Abstract
In the K/B×N mouse model of arthritis, autoantibodies against glucose-6-phosphate isomerase cause joint-specific inflammation and destruction. We have shown using micro-positron emission tomography that these glucose-6-phosphate isomerase-specific autoantibodies rapidly localize to distal joints of mice. In this study we used micro-positron emission tomography to delineate the stages involved in the development of arthritis. Localization of Abs to the joints depended upon mast cells, neutrophils, and FcRs, but not on C5. Surprisingly, anti-type II collagen Abs alone did not accumulate in the distal joints, but could be induced to do so by coinjection of irrelevant preformed immune complexes. Control Abs localized to the joint in a similar manner. Thus, immune complexes are essential initiators of arthritis by sequential activation of neutrophils and mast cells to allow Abs access to the joints, where they must bind a target Ag to initiate inflammation. Our findings support a four-stage model for the development of arthritis and identify checkpoints where the disease is reversible.
Stat3 Activation in Acute Lung Injury
Authors: Gao Hongwei , Guo Ren-Feng , Speyer Cecilia L. , Reuben Jayne , Neff Thomas A. , Hoesel L. Marco , Riedemann Niels C. , McClintock Shannon D. , Sarma J. Vidya , Van Rooijen Nico , Zetoune Firas S. , Ward Peter A. 
Published: April 2014

Abstract
Stat3 plays diverse roles in biological processes including cell proliferation, survival, apoptosis, and inflammation. Very little is known regarding its activation and function in the lung during acute inflammation. We now show that Stat3 activation was triggered in lungs and in alveolar macrophages after intrapulmonary deposition of IgG immune complexes in rats. Low levels of constitutive Stat3 were observed in normal rat lungs as determined by the EMSA. Stat3 activity in whole lung extracts increased 2 h after initiation of IgG immune complex deposition, reaching maximal levels by 4 h, whereas Stat3 activation was found in alveolar macrophages as early as 30 min after onset of injury. Expression and activation of Stat3 mRNA, protein, and protein phosphorylation was accompanied by increased gene expression of IL-6, IL-10, and suppressor of cytokine signaling-3 in whole lung tissues. Both Tyr705 and Ser727 phosphorylation were involved in Stat3 activation as assessed in whole lung extracts. C5a (complement 5, fragment a) per se can induce phosphorylation of Ser727 of Stat3. In vivo, Stat3 activation was dramatically suppressed by depletion of neutrophils or lung macrophages, resulting in reduced gene expression of IL-6 and IL-10 in whole lung tissues. Using blocking Abs to IL-6, IL-10, and C5a, Stat3 activation induced by IgG immune complexes was markedly diminished. These data suggest in the lung injury model used that activation of Stat3 in lungs is macrophage dependent and neutrophil dependent. IL-6, IL-10, and C5a contribute to Stat3 activation in inflamed rat lung.
IL-1β Impairs Insulin-Like Growth Factor I-Induced Differentiation and Downstream Activation Signals of the Insulin-Like Growth Factor I Receptor in Myoblasts
Authors: Broussard Suzanne R. , McCusker Robert H. , Novakofski Jan E. , Strle Klemen , Shen Wen Hong , Johnson Rodney W. , Dantzer Robert , Kelley Keith W. 
Published: April 2014

AbstractProinflammatory cytokines are elevated in disorders characterized by muscle wasting and weakness, such as inflammatory myopathies and AIDS wasting. We recently demonstrated that TNF-α impairs the ability of insulin-like growth factor (IGF)-I to promote protein synthesis in muscle precursor cells. In this study we extend these findings by showing that low concentrations of IL-1β impair IGF-I-dependent differentiation of myoblasts, as assessed by expression of the muscle specific protein, myosin heavy chain. In the absence of exogenous IGF-I, IL-1β (1 ng/ml) did not impair muscle cell development. However, in the presence of IGF-I, 100-fold lower concentrations of IL-1β (0.01 ng/ml) significantly suppressed myoblast differentiation, protein synthesis, and myogenin expression. Increasing IL-1β to 1 ng/ml completely blocked the anabolic actions of IGF-I in murine C2C12 myoblasts. Similarly, IL-1β inhibited IGF-I-stimulated protein synthesis in primary porcine myoblasts. IL-1β impaired the actions of IGF-I at a point distal to the IGF receptor, and this was not due to IL-1β-induced cell death. Instead, IL-1β inhibited the ability of IGF-I to phosphorylate tyrosine residues on both of its downstream docking proteins, insulin receptor substrate 1 and insulin receptor substrate 2. These data establish that physiological concentrations of IL-1β block the ability of IGF-I to promote protein synthesis, leading to reduced expression of the myogenic transcription factor, myogenin, and the subsequent development of more mature differentiated cells that express myosin heavy chain. Collectively, the results are consistent with the notion that very low concentrations of IL-1β significantly impair myogenesis, but they are unable to do so in the absence of the growth factor IGF-I.
Basophils Infiltrate Human Gastric Mucosa at Sites of Helicobacter pylori Infection, and Exhibit Chemotaxis in Response to H. pylori-derived Peptide Hp(2–20)
Authors: de Paulis Amato , Prevete Nella , Fiorentino Isabella , Walls Andrew F. , Curto Monica , Petraroli Angelica , Castaldo Vincenza , Ceppa Paola , Fiocca Roberto , Marone Gianni 
Published: April 2014

Abstract
Basophils, which are normally confined to the circulation, can migrate to sites of allergic inflammation. Using the specific mAb, BB1, we detected basophil infiltration of the gastric mucosa of Helicobacter pylori-infected patients affected by moderate and severe gastritis. Basophils were not found in H. pylori-free individuals or in subjects with mild gastritis. The H. pylori-derived peptide, Hp(2–20), was a potent basophil chemoattractant in vitro, whereas the control peptide, Hp1, was ineffective. Basophils from peripheral blood of healthy volunteers expressed mRNA for the formyl peptide receptors, N-formyl-peptide receptor (FPR), FPR-like (FPRL)1, and FPRL2. Preincubation of basophils with FMLP or Hp(2–20) caused complete desensitization to a subsequent challenge with homologous stimulus. Incubation of basophils with a low concentration of FMLP, which binds with high affinity to FPR, but not to FPRL1 or FPRL2, did not affect the chemotactic response to Hp(2–20). In contrast, a high concentration of FMLP, which binds to FPRL1 and FPRL2, reduced the chemotactic response to Hp(2–20). The FPR antagonist, cyclosporin H, prevented chemotaxis induced by FMLP, but not by Hp(2–20). Hp(2–20) could be responsible, at least in part, for basophil infiltration of the gastric mucosa of H. pylori-infected patients presumably through the interaction with FPRL1 and FPRL2.
Down-Regulation of IL-2 Production in T Lymphocytes by Phosphorylated Protein Kinase A-RIIβ
Authors: Elliott Michael R. , Shanks Ryan A. , Khan Islam U. , Brooks James W. , Burkett Pamela J. , Nelson Brandy J. , Kyttaris Vasileios , Juang Yuang-Taung , Tsokos George C. , Kammer Gary M. 
Published: April 2014

AbstractThe β isoform of the type II regulatory subunit (RIIβ) of protein kinase A suppresses CREB transcriptional activity and c-Fos production in T cells following activation via the TCR. Because CREB is an integral nuclear transcription factor for IL-2 production by T cells, we tested the hypothesis that RIIβ down-regulates IL-2 expression and IL-2 production in T cells. Stable transfection of RIIβ in Jurkat T cells led to an ∼90% reduction in IL-2 mRNA and IL-2 protein following T cell activation. The inhibition of IL-2 production was associated with phosphorylation of the RIIβ subunit at serine 114 (pRIIβ) and localization of pRIIβ in intranuclear clusters. A serine 114 phosphorylation-defective mutant, RIIβS114A, did not form these intranuclear clusters as well as wild-type RIIβ, and did not inhibit IL-2 mRNA and protein synthesis, indicating that serine 114 phosphorylation is required for both nuclear localization and down-regulation of IL-2 production by RIIβ. In contrast to its effect on IL-2, RIIβ induced constitutive up-regulation of CD154 mRNA and cell surface expression. Thus, pRIIβ differentially regulates gene expression following T cell activation. Unexpectedly, we also found that stable overexpression of another protein kinase A regulatory subunit, RIα, had the opposite effect on IL-2 expression, causing a 3- to 4-fold increase in IL-2 production following stimulation. In summary, our data demonstrate a novel mechanism by which serine 114 phosphorylation and nuclear localization of RIIβ controls the regulation of gene expression in T cells.
The Allograft Defines the Type of Rejection (Acute versus Chronic) in the Face of an Established Effector Immune Response
Authors: Chalasani Geetha , Li Qi , Konieczny Bogumila T. , Smith-Diggs Lonnette , Wrobel Barbara , Dai Zhenhua , Perkins David L. , Baddoura Fady K. , Lakkis Fadi G. 
Published: April 2014

Abstract
Transplanted organs fail due to either acute or chronic rejection. The prevailing view is that the nature or magnitude of the recipient’s immune response to donor Ags determines the type of rejection. In variance with this view, we show in this study that the status of the graft itself plays a dominant role in defining the type of rejection even in the face of an established alloimmune response. Using adoptive transfer mouse models in which the graft is exposed to a constant number of effector lymphocytes, we found that newly transplanted heart allografts are rejected acutely, while healed-in allografts undergo chronic rejection. Acute rejection of healed-in allografts was largely recapitulated by subjecting the grafts to ischemia-reperfusion injury similar to that present in newly transplanted organs. Ischemia-Reperfusion injury altered the outcome of rejection by enhancing the accumulation of effector T cells within the graft. The accumulation of effector T cells in the graft was dependent on the presence of both ischemia-reperfusion injury (inflammation) and alloantigens. These findings demonstrate that the graft plays a dominant role in shaping the outcome of rejection by controlling the trafficking of effector T cells.