bluuebunny/crossref_metadata_2025_split huggingface dataset:
RAW 264.7 macrophages induce apoptosis selectively in transformed fibroblasts: intercellular signaling based on reactive oxygen and nitrogen species
Authors: Heigold Stefanie , Bauer Georg 
Published: September 2022

AbstractThe rationale for this study was to determine whether macrophages induce apoptosis selectively in transformed compared with nontransformed fibroblasts and to elucidate the underlying intercellular signaling chemistry. Murine fibroblasts transformed by oncogene expression (ras, src) or methylcholanthrene treatment were sensitive for apoptosis induction by RAW 264.7 macrophages, whereas parental cells and revertants were insensitive. Moreover, RAW 264.7 macrophages induced apoptosis in normal rat kidney (NRK) fibroblasts transiently transformed by epidermal growth factor/transforming growth factor-β. Sensitivity for intercellular apoptosis induction was based on target cell-derived superoxide anions and effector cell-derived peroxidase and nitric oxide (NO). Superoxide anions dismutate to hydrogen peroxide, which is converted to HOCl by the peroxidase. The interaction of HOCl with superoxide anions then generates hydroxyl radicals. In parallel, NO interacts with superoxide anions and generates apoptosis-inducing peroxynitrite. Signaling by reactive oxygen and nitrogen species seems to represent a hitherto unrecognized signaling principle for the selective elimination of potential tumor cells by macrophages.
Potential role of the formyl peptide receptor-like 1 (FPRL1) in inflammatory aspects of Alzheimer's disease
Authors: Cui Youhong , Le Yingying , Yazawa Hiroshi , Gong Wanghua , Wang Ji Ming 
Published: September 2022

AbstractAlzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by the presence of multiple senile plaques in the brain tissue, which are also associated with considerable inflammatory infiltrates. Although the precise mechanisms of the pathogenesis of AD remain to be determined, the overproduction and precipitation of a 42 amino acid form of β amyloid (Aβ42) in plaques have implicated Aβ in neurodegeneration and proinflammatory responses seen in the AD brain. Our recent studies revealed that the activation of formyl peptide receptor-like 1 (FPRL1), a seven-transmembrane, G-protein-coupled receptor, by Aβ42 may be responsible for accumulation and activation of mononuclear phagocytes (monocytes and microglia). We further found that upon binding FPRL1, Aβ42 was rapidly internalized into the cytoplasmic compartment in the form of Aβ42/FPRL1 complexes. Persistent exposure of FPRL1-expressing cells to Aβ42 resulted in intracellular retention of Aβ42/FPRL1 complexes and the formation of Congo-red-positive fibrils in mononuclear phagocytes. Our observations suggest that FPRL1 may not only mediate the proinflammatory activity of Aβ42 but also actively participate in Aβ42 uptake and the resultant fibrillar formation. Therefore, FPRL1 may constitute an additional molecular target for the development of therapeutic agents for AD.
Hepatic natural killer cells exclusively kill splenic/blood natural killer-resistant tumor cells by the perforin/granzyme pathway
Authors: Vermijlen David , Luo Dianzhong , Froelich Christopher J , Medema Jan Paul , Kummer Jean Alain , Willems Erik , Braet Filip , Wisse Eddie 
Published: September 2022

AbstractHepatic natural killer (NK) cells are located in the liver sinusoids adherent to the endothelium. Human and rat hepatic NK cells induce cytolysis in tumor cells that are resistant to splenic or blood NK cells. To investigate the mechanism of cell death, we examined the capacity of isolated, pure (90%) rat hepatic NK cells to kill the splenic/blood NK-resistant mastocytoma cell line P815. Cell death was observed and quantified by fluorescence and transmission electron microscopy, DNA fragmentation, and 51Cr release. RNA and protein expression were determined by real time reverse transcription-polymerase chain reaction and Western blotting. Compared with splenic NK cells, hepatic NK cells expressed higher levels of perforin and granzyme B and readily induced apoptosis in P815 cells. Although P815 cells succumbed to recombinant Fas ligand (FasL) or isolated perforin/granzyme B, hepatic NK cells used only the granule pathway to kill this target. In addition, hepatic NK cells and sinusoidal endothelial cells strongly expressed the granzyme B inhibitor, protease inhibitor 9 (PI-9)/serine PI-6 (SPI-6), and P815 cells and hepatocytes were negative. Transfection of target cells with this inhibitor resulted in complete resistance to hepatic NK cell-induced apoptosis. In conclusion, hepatic NK cells kill splenic/blood NK-resistant/FasL-sensitive tumor cells exclusively by the perforin/granzyme pathway. Serine protease inhibitor PI-9/SPI-6 expression in liver sinusoidal endothelial cells may protect the liver microenvironment from this highly active perforin/granzyme pathway used to kill metastasizing cancer cells.
Calcium spikes in activated macrophages during Fcγ receptor-mediated phagocytosis
Authors: Myers Jesse T , Swanson Joel A 
Published: September 2022

AbstractRises in intracellular-free calcium ([Ca2+]i) have been variously associated with Fcγ receptor (FcR)-mediated phagocytosis in macrophages. We show here that activation of murine bone marrow-derived macrophages increases calcium spiking after FcR ligation. Ratiometric fluorescence microscopy was used to measure [Ca2+]i during phagocytosis of immunoglobulin G (IgG)-opsonized erythrocytes. Whereas 13% of nonactivated macrophages increased [Ca2+]i in the form of one or more spikes, 56% of those activated with lipopolysaccharides (LPS; 18 h at 100 ng/ml) and interferon-γ (IFN-γ; 100 U/ml) and 73% of macrophages activated with LPS, IFN-γ, interleukin (IL)-6 (5 ng/ml), and anti-IL-10 IgG (5 μg/ml) spiked calcium during phagocytosis. Calcium spikes were inhibited by thapsigargin (Tg), indicating that they originated from endoplasmic reticulum. The fact that activated macrophages showed a more dramatic response suggested that calcium spikes during phagocytosis mediate or regulate biochemical mechanisms for microbicidal activities. However, lowering [Ca2+]i with ethyleneglycol-bis(β-aminoethylether)-N,N′-tetraacetic acid or inhibiting calcium spikes with Tg did not inhibit phagosome-lysosome fusion or the generation of reactive oxygen or nitrogen species. Thus, the increased calcium spiking in activated macrophages was not directly associated with the mechanism of phagocytosis or the increased antimicrobial activities of activated macrophages.
Stimulation of neutrophil apoptosis by immobilized IgA
Authors: Schettini Jorge , Salamone Gabriela , Trevani Analía , Raiden Silvina , Gamberale Romina , Vermeulen Mónica , Giordano Mirta , Geffner Jorge R 
Published: September 2022

AbstractIn the current study, we analyzed whether immunoglobulin A (IgA) is able to modulate neutrophil apoptosis. We found that culture of neutrophils on immobilized plasma IgA (iIgAp) or secretory IgA (iIgAs) induced a marked increase in apoptotic rates. By contrast, soluble IgAp, IgAs, or aggregated IgAp exerted no effect. Promotion of apoptosis by iIgA was almost completely prevented by blocking antibodies directed to CD18 or CD11b and was shown to be dependent on the activation of the respiratory burst as suggested by the ability of catalase to prevent apoptosis stimulation; the effect of azide, an heme enzyme inhibitor that significantly increased promotion of apoptosis by iIgA; and the inability of iIgA to stimulate apoptosis of neutrophils isolated from chronic granulomatous disease patients. Stimulation of neutrophil apoptosis by IgA might contribute to the control of inflammatory processes in certain autoimmune diseases such as IgA nephropathy in which tissue deposits of IgA or IgA containing immune complexes are found.
MUC1 epithelial mucin (CD227) is expressed by activated dendritic cells
Authors: Wykes M , MacDonald K P A , Tran M , Quin R J , Xing P X , Gendler S J , Hart D N J , McGuckin M A 
Published: September 2022

AbstractThe MUC1 mucin (CD227) is a cell surface mucin originally thought to be restricted to epithelial tissues. We report that CD227 is expressed on human blood dendritic cells (DC) and monocyte-derived DC following in vitro activation. Freshly isolated murine splenic DC had very low levels of CD227; however, all DC expressed CD227 following in vitro culture. In the mouse spleen, CD227 was seen on clusters within the red pulp and surrounding the marginal zone in the white pulp. Additionally, we confirm CD227 expression by activated human T cells and show for the first time that the CD227 cytoplasmic domain is tyrosine-phosphorylated in activated T cells and DC and is associated with other phosphoproteins, indicating a role in signaling. The function of CD227 on DC and T cells requires further elucidation.
Increased PSGL-1 expression on granulocytes from allergic-asthmatic subjects results in enhanced leukocyte recruitment under flow conditions
Authors: Dang Bao , Wiehler Shahina , Patel Kamala D 
Published: September 2022

AbstractAllergic asthma is increasing in incidence and severity in many industrial countries. Leukocyte recruitment into the airways of affected individuals contributes to the severity of the disease. In this study, whole blood from normal, allergic, asthmatic, or allergic-asthmatic subjects was perfused over immobilized adhesion molecules using an in vitro flow chamber system to determine if there were differences in leukocyte recruitment in these patient populations. Leukocytes from allergic-asthmatic subjects showed a threefold increase in recruitment on P-selectin as compared with normal controls. In both patient populations, the accumulated cells were exclusively neutrophils and eosinophils. Increased granulocyte recruitment was specific for P-selectin, as neither purified E-selectin nor vascular cell adhesion molecule-1 (VCAM-1) supported enhanced leukocyte recruitment from allergic-asthmatics. Leukocyte accumulation on P-selectin was completely blocked by an anti-P-selectin or anti-P-selectin glycoprotein ligand-1 (PSGL-1) monoclonal antibody. Flow cytometry revealed that neutrophils and eosinophils from allergic-asthmatic subjects had increased expression of PSGL-1, whereas expression of another adhesion molecule, L-selectin, was unchanged. PSGL-1 expression on peripheral blood mononuclear cells of allergic-asthmatic patients was unaffected. The increased PSGL-1 expression on granulocytes from allergic-asthmatic patients also led to enhanced leukocyte recruitment on interleukin-4-stimulated human umbilical vein endothelial cells, which express P-selectin and VCAM-1. Thus, increased PSGL-1 expression on granulocytes from allergic-asthmatic subjects resulted in increased leukocyte recruitment on P-selectin under flow conditions.
Endotoxin induces rapid metalloproteinase-mediated shedding followed by up-regulation of the monocyte hemoglobin scavenger receptor CD163
Authors: Hintz Katharine A , Rassias Athos J , Wardwell Kathleen , Moss Marcia L , Morganelli Peter M , Pioli Patricia A , Givan Alice L , Wallace Paul K , Yeager Mark P , Guyre Paul M 
Published: September 2022

AbstractCD163, a monocyte and macrophage-specific surface glycoprotein, which is increased by interleukin-10 and glucocorticoids, is a scavenger receptor for hemoglobin/haptoglobin complexes. We report a rapid and highly reproducible rise in soluble CD163 in the plasma of human volunteers given intravenous lipopolysaccharide (LPS). We also show that LPS induces shedding of CD163 from the surface of isolated monocytes, identifying shedding from monocytes and macrophages as a likely mechanism for the endotoxemia-associated rise in plasma CD163 in vivo. Studies using the inhibitor TAPI-0 indicate that a metalloproteinase is responsible for LPS-mediated shedding of CD163. Finally, we demonstrate a marked increase in surface CD163 expression on circulating monocytes 24 h following experimental endotoxemia. These findings show that CD163 is rapidly mobilized in response to bacterial endotoxin. As hemoglobin can bind LPS and enhance its toxicity, it will be important to determine how cell surface and soluble CD163 influence inflammatory processes during sepsis.
IFN-γ and IL-12 differentially regulate CC-chemokine secretion and CCR5 expression in human T lymphocytes
Authors: Losana Giuliana , Bovolenta Chiara , Rigamonti Laura , Borghi Igor , Altare Frederic , Jouanguy Emmanuelle , Forni Guido , Casanova Jean-Laurent , Sherry Barbara , Mengozzi Manuela , Trinchieri Giorgio , Poli Guido , Gerosa Franca , Novelli Francesco 
Published: September 2022

AbstractInterleukin (IL)-12, especially in the presence of neutralizing anti-IL-4 monoclonal antibodies, primed CD45RO− T clones for high CCL3/macrophage-inflammatory protein-1α (MIP-1α) and CCL4/MIP-1β levels. In CD4+ and CD8+ clones from two patients deficient for IL-12Rβ1 (IL-12Rβ1−/−), production of CCL3/MIP-1α and CCL4/MIP-1β was defective. CD4+ clones from two patients deficient for interferon-γ (IFN-γ) R1 (IFN-γR1−/−) produced somewhat decreased CCL4/MIP-1β levels. IL-12 failed to prime CD4+ or CD8+ healthy clones for high CCL5/regulated on activation, normal T expressed and secreted (RANTES) production, although its secretion was impaired in CD4+ clones from IL-12Rβ1−/− and IFN-γR1−/− patients. CCR5 surface expression was up-regulated in resting peripheral blood mononuclear cells and CD4+ clones from both kinds of patients, rendering them more susceptible to CCR5-dependent (R5) HIV-1 infection. Neutralization of IFN-γ increased CCR5 expression and decreased CC-chemokine secretion by CD4+ clones from healthy and IL-12Rβ1−/− individuals, suggesting an IFN-γ-dependent control of CCR5 expression. These data provide the first documented analysis of chemokine secretion and chemokine receptor expression on T cells from IL-12 and IFN-γ receptor-deficient patients and dissect the role of IL-12 and IFN-γ on inducing inflammatory chemokine secretion and down-regulating CCR5 expression in human T cells.
Phosphorylation-dependent interaction of osteopontin with its receptors regulates macrophage migration and activation
Authors: Weber Georg F , Zawaideh Samer , Hikita Sherry , Kumar Vikram A , Cantor Harvey , Ashkar Samy 
Published: September 2022

AbstractNeutrophil-independent macrophage responses are a prominent part of delayed-type immune and healing processes and depend on T cell-secreted cytokines. An important mediator in this setting is the phosphoprotein osteopontin, whose secretion by activated T cells confers resistance to infection by several intracellular pathogens through recruitment and activation of macrophages. Here, we analyze the structural basis of this activity following cleavage of the phosphoprotein by thrombin into two fragments. An interaction between the C-terminal domain of osteopontin and the receptor CD44 induces macrophage chemotaxis, and engagement of β3-integrin receptors by a nonoverlapping N-terminal osteopontin domain induces cell spreading and subsequent activation. Serine phosphorylation of the osteopontin molecule on specific sites is required for functional interaction with integrin but not CD44 receptors. Thus, in addition to regulation of intracellular enzymes and substrates, phosphorylation also regulates the biological activity of secreted cytokines. These data, taken as a whole, indicate that the activities of distinct osteopontin domains are required to coordinate macrophage migration and activation and may bear on incompletely understood mechanisms of delayed-type hypersensitivity, wound healing, and granulomatous disease.
Endothelial Rho and Rho kinase regulate neutrophil migration via endothelial myosin light chain phosphorylation
Authors: Saito Hajime , Minamiya Yoshihiro , Saito Satoshi , Ogawa Jun-ichi 
Published: September 2022

AbstractThe transendothelial migration of neutrophils is a critical step in acute inflammation, which we previously showed to be regulated by endothelial myosin light chain (MLC) kinase. Recent studies suggest that Rho and Rho kinase are also key mediators of MLC phosphorylation, but their roles in neutrophil migration have not been investigated. In the present study, a transwell chamber migration assay system incorporating endothelial monolayer was used to examine the numbers of migrating neutrophils, endothelial F-actin and myosin II rearrangement, and endothelial MLC phosphorylation at selected times during the neutrophil migration in vitro. The results showed that pretreating endothelial cells with C3 (Rho inhibitor) or Y-27632 (Rho kinase inhibitor) significantly diminished neutrophil migration, actin polymerization, myosin II filament formation, and MLC phosphorylation normally associated with the migration. These data suggest that endothelial Rho and Rho kinase regulate transendothelial neutrophil migration by modulating the cytoskeletal events that mediate such migration.
Increased function and survival of IL-15-transduced human dendritic cells are mediated by up-regulation of IL-15Rα and Bcl-2
Authors: Tourkova Irina L , Yurkovetsky Zoya R , Gambotto Andrea , Makarenkova Valeria P , Perez Lori , Balkir Levent , Robbins Paul D , Shurin Michael R , Shurin Galina V 
Published: September 2022

AbstractIt has been recently demonstrated that dendritic cells (DC) coincubated with interleukin (IL)-15 express high levels of the Bcl-2 family of proteins and display an increased resistance to tumor-induced apoptotic death. Here, the phenotype, functions, and survival of human DC transduced with adenoviral vector encoding the human IL-15 gene were studied. The transduction of DC with the IL-15 gene resulted in a significant elevation of expression of CD83, CD86, and CD40 molecules, which was blocked by anti-IL-15 monoclonal antibodies. This effect was also accompanied by an increased production of IL-12 and stimulated ability of DC to induce T cell proliferation. Furthermore, transduction of DC with the IL-15 gene significantly increased their resistance to prostate cancer-induced apoptosis: Overexpression of IL-15 on DC blocked tumor-induced inhibition of Bcl-2 expression and prolonged DC survival after coincubation with tumor cells. Finally, overexpression of IL-15 in DC was associated with a higher level of expression of IL-15 receptor α chain mRNA. In summary, these results suggest that transduction of DC with the IL-15 gene markedly stimulates DC function and protects them from tumor-induced apoptosis.
Multiple determinants are involved in HIV coreceptor use as demonstrated by CCR4/CCL22 interaction in peripheral blood mononuclear cells (PBMCs)
Authors: Agrawal Lokesh , Vanhorn-Ali Zainab , Alkhatib Ghalib 
Published: September 2022

AbstractAlthough a number of chemokine receptors display coreceptor activities in vitro, chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 (CXCR4) remain the major coreceptors used by the human immunodeficiency virus type 1 (HIV-1). In this study, we used an envelope-mediated fusion assay to demonstrate low CCR4 coreceptor activity with some primary HIV-1 and simian immunodeficiency virus-1 (mac316) isolates in vitro. The coreceptor activity was sensitive to CCR4-specific antibodies and to the CCR4-specific chemokine ligand macrophage-derived chemokine (MDC)/chemokine ligand 22 (CCL22). Treatment of peripheral blood mononuclear cells (PBMCs; which express high levels of CCR4) with CCL22 caused down-modulation of endogenous CCR4 but had no significant effect on HIV-1 entry, suggesting that CCR4 may not be used as an entry coreceptor. Despite expression of other minor coreceptors on PBMCs, CCR5 and CXCR4 are preferentially used by HIV-1 isolates, as shown by chemokine-inhibition data. To determine the factors involved in this selective use, we analyzed CCR4 coreceptor activity and compared it with CCR5 use in PBMCs. We used a quantitative fluorescence-activated cell-sorting assay to estimate the numbers of CCR4 and CCR5 antibody-binding sites (ABS) on PBMCs. Although CCR4 was found on a higher percentage of CD4(+) cells, CCR5 ABS was twofold greater than CCR4 ABS on CD4(+) cells. Confocal microscopy revealed strong cell-surface CD4/CCR5 but weak CD4/CCR4 colocalization in PBMCs. Binding studies demonstrated that soluble gp120 had greater affinity to CCR5 than CCR4. The results suggested that coreceptor density, colocalization with CD4, and affinity of the viral gp120 to the coreceptor may determine preferential coreceptor use by HIV-1.
Donor T cell and host NK depletion improve the therapeutic efficacy of allogeneic bone marrow cell reconstitution in the nonmyeloablatively conditioned tumor-bearing host
Authors: Hummel Susanne , Wilms Daniela , Vitacolonna Mario , Zöller Margot 
Published: September 2022

AbstractAllogeneic bone marrow cell reconstitution of the nonmyeloablatively conditioned host has the advantage that it can be tolerated in suboptimal health conditions. However, the problem of graft versus host disease (GvHD) remains. Also, graft acceptance may become delicate, and HvGD may arise. We report here on advantages/disadvantages of host natural killer (NK) depletion and graft T cell depletion in fully allogeneic, healthy and solid tumor-bearing mice. NK depletion of the “healthy” host improved the survival rate, whereas graft T cell depletion was disadvantageous. In the tumor-bearing host, graft T cell depletion was beneficial when the host was NK-depleted. Host NK depletion facilitated B lymphopoiesis, repopulation of the thymus, expansion of donor cells, and tolerance induction. The disadvantage of graft T cell depletion in the “healthy” host was a result of delayed engraftment. Because in tumor-bearing mice, host but not graft hematopoiesis was strongly impaired, donor hematopoiesis dominated. Graft T cell depletion reduced GvHD but hardly interfered with engraftment. Importantly, graft-mediated tumor reactivity appeared late and was unimpaired when the graft was T cell-depleted. Thus, concomitant depletion of host NK and donor T cells is advantageous when approaching therapeutic treatment of solid tumors by allogeneic reconstitution of the nonmyeloablatively conditioned host.
Restricted replication of primary HIV-1 isolates using both CCR5 and CXCR4 in Th2 but not in Th1 CD4+ T cells
Authors: Vicenzi Elisa , Panina-Bodignon Paola , Vallanti Giuliana , Di Lucia Pietro , Poli Guido 
Published: September 2022

AbstractWe have previously reported that CCR5-dependent human immunodeficiency virus type-1 (HIV-1; R5), but not CXCR4-restricted (X4) virus, efficiently replicates in T helper cell type 1 (Th1), Th2, or Th0 polyclonal T cells obtained from human umbilical cord blood (CB lines). The X4 virus restriction was env-dependent but did not occur at the level of viral entry. Here, we describe that in contrast to these monotropic HIVs, primary HIV-1 isolates capable of using CCR5 or CXCR4 indifferently for entry (i.e., R5X4 viruses) efficiently replicated in Th2 but not in Th1 CB lines. Although Th1 cells secreted significantly higher amounts of the three CCR5-binding chemokines in comparison with Th2 cells, this restriction was not explained by a defective infection of Th1 cells. Interferon-γ (IFN-γ) down-regulated CCR5 in Th1 cells and inhibited, whereas interleukin-4 (IL-4) up-regulated CXCR4 and enhanced the spreading of R5 and R5X4 viruses in polarized CB lines. However, both cytokines did not rescue the replication of X4 and dualtropic viruses in both types of CB lines or in Th1 cells, respectively, whereas addition of anti-IL-4- or anti-IFN-γ-neutralizing antibodies did not activate virus expression. These findings together suggest the existence of post-entry restriction pathways influenced by gp120 Env/chemokine coreceptor interaction that may significantly contribute to the superior capacity of R5 and R5X4 HIV-1 strains to spread in vivo in comparison to X4 monotropic viruses.