bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spontaneous apoptosis in neutrophils is associated with downregulation of HLA Class I and is prevented by ligation of Class I
Authors: Frumento Guido , Ottonello Luciano , Bertolotto Maria , Franchello Silvia , Melioli Giovanni , Dallegri Franco 
Published: September 2022

AbstractIn many types of cells, ligation of human leukocyte antigens (HLA) Class I molecules with specific mAbs results in the transduction of signals that trigger different cell functions. We have investigated the effects of Class I ligation in human neutrophils. After several hours in culture, neutrophils split spontaneously into two subpopulations, one with normal and the other with reduced levels of Class I. The latter subpopulation displayed high binding capacity for Annexin V, showed a hypodiploid peak, electrophoretic DNA fragmentation, and morphological features of apoptotic cells. The addition of drugs known to delay apoptosis (GM-CSF or cAMP) resulted in a reduction of Class I modulation. Furthermore, ligation of surface Class I with F(ab′)2 fragments of the anti-Class I mAb W6/32 resulted in a delay in the progression of apoptosis. These data indicate that this surface Class I molecule is a marker of age-related apoptosis, and the ligation of these molecules results in the transduction of a signal that inhibits apoptosis. Thus, the downregulation of HLA Class I molecules in aging neutrophils prevents their halting the apoptotic process.
Monocytes adhering by LFA-1 to placental syncytiotrophoblasts induce local apoptosis via release of TNF-α. A model for hematogenous initiation of placental inflammations
Authors: Garcia-Lloret Maria I , Winkler-Lowen Bonnie , Guilbert Larry J 
Published: September 2022

AbstractPlacental inflammations (villitis) are accompanied by loss of the syncytiotrophoblast, which is the cellular barrier separating maternal blood from fetal tissue in the villous placenta. We propose that syncytiotrophoblast loss is mediated by adhesion of activated maternal monocytes. This hypothesis was tested with a co-culture model of peripheral blood monocytes and placental syncytiotrophoblasts. We find that LPS-activated monocytes adhere to interferon-γ (IFN-γ)-treated syncytiotrophoblasts via monocyte LFA-1 for &gt;48 h, during which time the monocytes induce trophoblast apoptosis and subsequent damage of the trophoblast layer. Optimal monocyte-mediated syncytiotrophoblast death requires both lipopolysaccharide (LPS) and IFN-γ and is inhibited by either anti-tumor necrosis factor (TNF) antibody or epidermal growth factor. Syncytiotrophoblast damage is largely limited to culture surfaces in the vicinity of bound monocytes. These results show that activated maternal monocytes bound to the placental barrier can induce focal damage mediated by the inflammatory cytokine TNF-α and suggest a route for maternal leukocyte infiltration into the fetal stroma.
Transcriptional activation of the gp91phoxNADPH oxidase subunit by TPA in HL-60 cells
Authors: Samuelson David J , Powell Marianne-B , Lluria-Prevatt Maria , Romagnolo Donato F 
Published: September 2022

AbstractThe exposure to epigenetic effectors capable of inducing copious production of reactive oxygen species (ROS) has been associated with chronic inflammation, tumor initiation, and promotion. The objective of this study was to examine the regulation of gp91phox, the catalytic subunit of the NADPH oxidase, and the kinetics of ROS production in promyelocytic leukemia HL-60 cells induced with 12-O-tetradeconylphorbol-13-acetate (TPA). The treatment of HL-60 cells with TPA (0.1 μM) induced cellular differentiation, which was followed after 48 h by a tenfold increase in chemiluminescence from lucigenin and a 2.5-fold increase in the intracellular oxidation of 2′,7′-dicholorofluorescin (DCFH). Whereas higher concentrations (1.0 μM) of TPA did not stimulate further ROS production, repeated stimulation with 0.1 μM TPA of differentiated cells induced a modest (1.2-fold) but rapid (15 min) increase in chemiluminescence. In cells treated with TPA, the burst in ROS at 48 h was preceded by accumulation at 12 h of gp91phox (8.8-fold) and p47phox mRNA (threefold), whereas untreated cells contained steady-state levels of both transcripts. Time-course experiments with actinomycin D to inhibit transcription revealed that TPA did not improve the stability of gp91phox. In transient transfections, luciferase reporter activity directed from a 1.5-kb gp91phox promoter fragment was enhanced threefold upon treatment with TPA for 24 h. We conclude that TPA can commit HL-60 cells to differentiation and elicit transcription from the proximal gp91phox promoter.
PAF-mediated Ca2+ influx in human neutrophils occurs via store-operated mechanisms
Authors: Hauser Carl J , Fekete Zoltan , Adams John M , Garced Matthew , Livingston David H , Deitch Edwin A 
Published: September 2022

AbstractMany inflammatory mediators activate neutrophils (PMN) partly by increasing cytosolic calcium concentration ([Ca2+]i). Modulation of PMN [Ca2+]i might therefore be useful in regulating inflammation after shock or sepsis. The hemodynamic effects of traditional Ca2+ channel blockade, however, could endanger unstable patients. Store-operated calcium influx (SOCI) is known now to contribute to Ca2+ flux in “nonexcitable” cells. Therefore, we studied the role of SOCI in human PMN responses to the proinflammatory ligand PAF. PMN [Ca2+]i was studied by spectrofluorometry with and without external calcium. We studied the effects of PAF on Mn2+ entry into and on Ca2+ efflux from thapsigargin (Tg)-treated cells. Influx was assessed in the presence and absence of the blockers SKF-96365 (SKF), TMB-8, and 2-APB. Half of PAF [Ca2+]i mobilization occurs via calcium influx. The kinetics of calcium entry were typical of SOCI rather than receptor-mediated calcium entry (RMCE). SKF had multiple nonspecific effects on [Ca2+]i. Inhibition of store emptying by TMB-8 and 2-APB blocked all calcium entry, demonstrating influx was store depletion-dependent. PAF has no direct effect on calcium efflux. Where SOCI is maximal, PAF has no further effect on calcium-channel traffic. PAF-induced calcium signals are highly dependent on SOCI and independent of RMCE. SOCI-specific blockade might modulate PMN-mediated inflammation and spare cardiovascular function in shock and sepsis.
Severe exercise enhances phagocytosis by murine bronchoalveolar macrophages
Authors: Su Shu-Hui , Chen Hsiun-ing , Jen Chauying J 
Published: September 2022

AbstractBecause physical activity affects the immune competency of individuals by an unknown mechanism, we investigated the effect of acute exercise on phagocytosis of bronchoalveolar macrophages (BAMs). Male BALB/c mice, 7–9 weeks old, ran on a treadmill to exhaustion (severe exercise, SE) or at a final speed of 17 m/min for 30 min (moderate exercise, ME). Although both exercise protocols induced differential leukocytosis, 95% leukocytes from lung lavages of both groups were BAMs. The BAM phagocytic capacity of nonopsonized beads increased immediately after SE but not after ME, gradually returning to the basal level after 4 h. SE upregulates the macrophage scavenger receptors (SR-A type I/II and MARCO), CR3, and ICAM-1, but not FcγR. Although the blocking effect of MARCO antibody was most pronounced, that of ICAM-1 antibody was totally reversed by cross-linking CR3. Our results showed that SE, but not ME, activated BAMs and that the enhanced nonopsonized phagocytosis was mainly mediated by scavenger receptors and ICAM-1/CR3.
Subthreshold concentrations of anti-proteinase 3 antibodies (c-ANCA) specifically prime human neutrophils for fMLP-induced leukotriene synthesis and chemotaxis
Authors: Hattar Katja , Sibelius Ulf , Bickenbach Annette , Csernok Elena , Seeger Werner , Grimminger Friedrich 
Published: September 2022

AbstractAnti-neutrophil cytoplasmic antibodies (ANCA) targeting proteinase 3 (PR3) possess a high sensitivity and specificity for Wegener's granulomatosis. Due to their capacity of directly activating neutrophils, a pathogenetic role for these autoantibodies has been proposed. We investigated the impact of subthreshold concentrations of monoclonal anti-PR3 antibodies (anti-PR3; 0.1 μg/mL) on neutrophil activation elicited by a secondary agent. Preincubation with anti-PR3 resulted in a massive amplification of N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced leukotriene (LT) generation, with a marked increase in the liberation of LTB4, LTA4, and 5-hydroxyeicosatetraenoic acid (5-HETE). This priming commenced within 2.5 min, with a maximum after 5–7.5 min. Moreover, anti-PR3 pretreatment markedly enhanced PMN movement toward fMLP. The priming effect of anti-PR3 toward fMLP challenge was reproduced by c-ANCA, but not by F(ab)2 fragments of the antibodies and isotype-matched control IgG. Generation of superoxide anion and release of elastase were suppressed in anti-PR3-pretreated neutrophils undergoing fMLP challenge. In contrast, neutrophil activation by platelet-activating factor (PAF) or the calcium ionophore A23187 remained unaffected. We conclude that subthreshold concentrations of anti-PR3 antibodies selectively modify neutrophil responses to fMLP, with enhancement of leukotriene generation and chemotaxis, but suppression of respiratory burst and degranulation. Such priming might contribute to localized neutrophil accumulation together with blunted host defense in Wegener's granulomatosis.
Inhibitory effect of serine protease inhibitors on neutrophil-mediated endothelial cell injury
Authors: Nakatani Keigo , Takeshita Seiichiro , Tsujimoto Hiroshi , Kawamura Youichi , Sekine Isao 
Published: September 2022

AbstractTo investigate the inhibitory effect of serine protease inhibitors (SPI) on neutrophil-mediated endothelial cell (EC) injury, we analyzed the in vitro cytotoxicity of radiolabeled human umbilical vein EC (HUVEC) mediated by neutrophils in the presence of SPI. The EC injury was inhibited dose-dependently by urinary trypsin inhibitor (ulinastatin, UTI) and ONO-5046, which have the ability to inactivate neutrophil elastase, but not by gabexate mesilate, nafamostat mesilate, aprotinin, and argatroban, which have no ability to inactivate neutrophil elastase. In addition, when UTI and ONO-5046 were added to the tumor necrosis factor α-primed neutrophils alone, they showed a dose-dependent inhibition of the intracellular elastase activity, but the other SPI did not, for either flow cytometry or confocal microscopy. Therefore, UTI and ONO-5046 may protect EC against the neutrophil-mediated injury not only by inactivating the extracellular elastase secreted by neutrophils, but also by acting directly on neutrophils and suppressing the production and secretion of activated elastase from them.
Colostral neutrophils express Fcα receptors (CD89) lacking γ chain association and mediate noninflammatory properties of secretory IgA
Authors: Honorio-França Adenilda C , Launay Pierre , Carneiro-Sampaio Magda M S , Monteiro Renato C 
Published: September 2022

AbstractColostrum plays an important role in protecting newborn infants against acute gastrointestinal and respiratory infections. IgA antibodies have been considered the major effector component; however, the role of their receptors on colostral phagocytes, especially neutrophils, has not been studied. Here, we demonstrate that CD15+ colostrum neutrophils express IgA Fc receptors (FcαR, CD89) at levels similar to those of blood neutrophils. Most colostral cells (70%) bear secretory IgA (SIgA) on their surface (and intracellularly), whereas blood cells do not. The FcαR on colostral neutrophils was identified as the a.1 isoform with a similar molecular mass (55–75 kDa) as that identified for blood neutrophils. Removal of N-linked carbohydrates revealed a major protein core of 32 kDa for both cell types. In contrast, co-immunoprecipitation and immunoblot experiments using a mild detergent, digitonin, revealed a lack of γ chain association with FcαR (γ-less) exclusively on colostral neutrophils. The functional role of these γ-less FcαR cells was evaluated by measuring superoxide release and killing of SIgA-coated enteropathogenic E. coli. No increase in superoxide release was observed in colostral cells compared with blood neutrophils, whereas optimal release was obtained with PMA stimulation. Furthermore, despite similar bacterial phagocytosis index between both cell types, IgA-mediated bacterial-killing was not detectable with colostral neutrophils, whereas killing was detectable on blood cells. These results reveal exclusive expression of γ-less FcαR on colostral neutrophils associated with receptor hyperoccupation by IgA and with low, bacterial-killing activity, which suggest that this receptor may mediate noninflammatory effects of SIgA.
The endotoxin-binding bactericidal/permeability-increasing protein (BPI): a target antigen of autoantibodies
Authors: Schultz H , Weiss J , Carroll S F , Gross W L 
Published: September 2022

AbstractThe bactericidal/permeability-increasing protein (BPI) is anendotoxin-binding neutrophil leukocyte-granule protein withantibacterial and anti-endotoxin properties. A recombinant form of BPI(rBPI21) has been developed and is being tested as atherapeutic agent to treat Gram-negative bacterial infections andexposure to Gram-negative bacterial endotoxin. BPI is also a targetantigen of anti-neutrophil cytoplasmic autoantibodies (ANCA). BPI-ANCAare present in cystic fibrosis, inflammatory bowel disease, vasculitis,and primary sclerosing cholangitis; presence of BPI-ANCA appearsassociated with a higher inflammatory disease activity and greaterorgan damage. BPI-ANCA as well as ANCA directed at otherneutrophil-granule proteins may exacerbate inflammation by nonspecificeffects of extracellular and cell-associated immune complexes. BPI-ANCAmay further worsen inflammation by reducing the ability of BPI topromote clearance of Gram-negative bacteria and bacterial-associatedendotoxin.
Changes of HSP72-expression in leukocytes are associated with adaptation to exercise under conditions of high environmental temperature
Authors: Fehrenbach Elvira , Niess Andreas Michael , Veith Roman , Dickhuth Hans-Herrmann , Northoff Hinnak 
Published: September 2022

AbstractOverexpression of the heat shock protein HSP72 providesthermotolerance. We asked if two consecutive endurance runs 1 weekapart (CR1, CR2) and additional environmental heat stress affectHSP72-expression in leukocytes of nonheat-acclimated enduranceathletes. Twelve subjects were allocated randomly into two groups. Group HH completed both runs at 28°C ambient temperature, and groupNH performed CR1 at 18°C and CR2 at 28°C. HSP72-expression wasdetermined by flow cytometry and RT-PCR before and 0, 24, and 48 hafter exercise. Additionally, post-exercise cells were exposed toin vitro heat shock (HS; 2 h, 42°C). The prolonged, high HSP72 protein level after CR1 in HH compared with NH may reflectthermotolerance induced by endurance exercise at high ambienttemperature. Adaptation of cardiocirculatory/thermoregulatory capacityafter CR2 in HH went along with a more rapid down-regulation of HSP72compared with CR1. HSP72 mRNA demonstrated temperature-related changesafter exercise. The reduced HS response in vitro after CR2may represent exercise-related adaptation mechanisms. HSP72concentrations in leukocytes may indicate previous exercise- andtemperature-related stress conditions and adaptation in immunocompetentcells.
Quantitative analysis of chemokine expression by dendritic cell subsets in vitro and in vivo
Authors: Vissers Joost L M , Hartgers Franca C , Lindhout Ernst , Teunissen Marcel B M , Figdor Carl G , Adema Gosse J 
Published: September 2022

AbstractUpon maturation, dendritic cells (DCs) have to adjust their chemokineexpression to sequentially attract different leukocyte subsets. We usedreal-time quantitative polymerase chain reaction analysis to study indetail the expression of 12 chemokines involved in the recruitment ofleukocytes into and inside secondary lymphoid organs, by DCs indistinct differentiation stages, both in vitro and in vivo. Monocyte-derived immature DCs expressed high levels of DCchemokine 1 (DC-CK1), EBI1-ligand chemokine (ELC), macrophage-derivedchemokine (MDC), macrophage-inflammatory protein (MIP)-1α, and thymusand activation-regulated chemokine (TARC). Upon maturation, DCsup-regulated the expression of DC-CK1 (60-fold), ELC (7-fold), and TARC(10-fold). Activation of DCs by CD40 ligand further up-regulated theexpression of ELC (25-fold). We found that freshly isolated blood DCsexpressed only low levels of interleukin-8, lymphotactin, and MIP-1α. It is interesting that the chemokine profile expressed by activatedCD11c− lymphoid-like as well as CD11c+ myeloidblood DCs mimics that of monocyte-derived DCs. Additionally, purifiedLangerhans cells that had migrated out of the epidermis expressed asimilar chemokine pattern. These data indicate that different DCsubsets in vitro and in vivo can express the same chemokines to attractleukocytes.
Peroxynitrite mediates cytokine-induced IL-8 gene expression and production by human leukocytes
Authors: Zouki Christine , József Levente , Ouellet Sophie , Paquette Yves , Filep János G 
Published: September 2022

AbstractRecent studies indicate that nitric oxide (NO) or related compounds mayregulate the production of interleukin (IL)-8, a potent proinflammatorychemokine. Here we report that peroxynitrite (ONOO−)formed by a reaction of NO with superoxide mediates IL-8 geneexpression and IL-8 production in IL-1β- and TNF-α-stimulated humanleukocytes in whole blood. The NO synthase inhibitors aminoguanidineand NG-nitro-l-arginine methylester blocked nuclear accumulation of activator protein-1 (AP-1) andnuclear factor (NF)-κB in both polymorphonuclear (PMN) andmononuclear leukocytes and inhibited IL-8 mRNA expression and IL-8release by ∼90% in response to IL-1β and TNF-α. EnhancedONOO− formation was detected in granulocytes, monocytes, and lymphocytes after challenge with IL-1β or TNF-α. The additionof ONOO− (0.2–80 μM) to whole blood increased nuclearaccumulation of AP-1 and NF-κB in PMN and mononuclear leukocytes andaugmented IL-8 mRNA expression and IL-8 production in aconcentration-dependent fashion. Pyrrolidine dithiocarbamate, aninhibitor of NF-κB activation, attenuated ∼70% of IL-8 releaseevoked by IL-1β, TNF-α, or ONOO−. These resultsindicate that ONOO− formation may underlie the action ofcytokines towards IL-8 gene expression in human leukocytes.
Combinatorial signals by inflammatory cytokines and chemokines mediate leukocyte interactions with extracellular matrix
Authors: Vaday Gayle G , Franitza Susanne , Schor Hagai , Hecht Iris , Brill Alexander , Cahalon Liora , Hershkoviz Rami , Lider Ofer 
Published: September 2022

AbstractOn their extravasation from the vascular system into inflamed tissues, leukocytes must maneuver through a complex insoluble network of molecules termed the extracellular matrix (ECM). Leukocytes navigate toward their target sites by adhering to ECM glycoproteins and secreting degradative enzymes, while constantly orienting themselves in response to specific signals in their surroundings. Cytokines and chemokines are key biological mediators that provide such signals for cell navigation. Although the individual effects of various cytokines have been well characterized, it is becoming increasingly evident that the mixture of cytokines encountered in the ECM provides important combinatorial signals that influence cell behavior. Herein, we present an overview of previous and ongoing studies that have examined how leukocytes integrate signals from different combinations of cytokines that they encounter either simultaneously or sequentially within the ECM, to dynamically alter their navigational activities. For example, we describe our findings that tumor necrosis factor (TNF)-α acts as an adhesion-strengthening and stop signal for T cells migrating toward stromal cell-derived factor-1α, while transforming growth factor-β down-regulates TNF-α-induced matrix metalloproteinase-9 secretion by monocytes. These findings indicate the importance of how one cytokine, such as TNF-α, can transmit diverse signals to different subsets of leukocytes, depending on its combination with other cytokines, its concentration, and its time and sequence of exposure. The combinatorial effects of multiple cytokines thus affect leukocytes in a step-by-step manner, whereby cells react to cytokine signals in their immediate vicinity by altering their adhesiveness, directional movement, and remodeling of the ECM.
TSG-14 transgenic mice have improved survival to endotoxemia and to CLP-induced sepsis
Authors: Dias Adriana A M , Goodman Adam R , Dos Santos Jane Lima , Gomes Rachel Novaes , Altmeyer Anne , Bozza Patrícia T , de Fátima Horta Maria , Vilcek Jan , Reis Luiz F L 
Published: September 2022

AbstractTumor necrosis factor-stimulated gene 14 (TSG-14)/PTX3 was identifiedoriginally as a TNF-α and IL-1β-stimulated gene from normal, humanforeskin fibroblasts and vascular endothelial cells, respectively. TSG-14 gene encodes a 42-kDa-secreted glycoprotein with acarboxy-terminal half that shares homology with the entire sequence of C-reactive protein (CRP) and serum amyloid P component (SAP),acute-phase proteins of the pentraxin family. Some experimentalevidence suggests that TSG-14 plays a role in inflammation, yet itsfunction and mechanism of action remain unclear. We have generatedtransgenic mice that overexpress the murine TSG-14 gene under thecontrol of its own promoter. From eight transgenic founders, twolineages were derived and better characterized: Tg2 and Tg4, carryingtwo and four copies of the transgene, respectively. TSG-14 transgenicmice were found to be more resistant to the endotoxic shock induced byLPS and to the polymicrobial sepsis caused by cecal ligation andpuncture (CLP). Moreover, macrophages derived from the transgenic miceproduced higher amounts of nitric oxide in response to IFN-γ,TNF-α, and LPS as compared with macrophages from wild-type animals, and the augmented response appears to be the consequence of a higherresponsiveness of transgenic macrophages to IFN-γ. The data shownhere are the first in vivo evidence of the involvement of TSG-14 in the inflammatory process and suggest a role for TSG-14 in thedefense against bacterial infections.
CD8α− and CD8α+ subclasses of dendritic cells undergo phenotypic and functional maturationin vitroandin vivo
Authors: De Smedt Thibaut , Butz Eric , Smith Jeffrey , Maldonado-López Roberto , Pajak Bernard , Moser Muriel , Maliszewski Charles 
Published: September 2022

AbstractDendritic cells (DCs) are essential for the priming of immune responses. This antigen-presenting function of DCs develops in sequence in a process called maturation, during which they become potent sensitizers of naïve T cells but reduce their ability to capture and process antigens. Some heterogeneity exists in mouse-DC populations, and two distinct subsets of DCs expressing high levels of CD11c can be identified on the basis of CD8α expression. We have studied the phenotype and maturation state of mouse splenic CD8α− and CD8α+ DCs. Both subsets were found to reside in the spleen as immature cells and to undergo a phenotypic maturation upon culture in vitro in GM-CSF-containing medium or in vivo in response to lipopolysaccharide. In vitro and in vivo analyses showed that this maturation process is an absolute requisite for DCs to acquire their T-cell priming capacity, transforming CD8α− and CD8α+ DCs into potent and equally efficient activators of naïve CD4+ and CD8+ T cells. Furthermore, these results highlight the importance that environmental factors may have on the ability of DC subsets to influence Th responses qualitatively; i.e., the ability to drive Th1 versus Th2 differentiation may not be fixed immutably for each DC subset.