bluuebunny/crossref_metadata_2025_split huggingface dataset:
The human EGF-TM7 family member EMR2 is a heterodimeric receptor expressed on myeloid cells
Authors: Kwakkenbos Mark J , Chang Gin-Wen , Lin Hsi-Hsien , Pouwels Walter , de Jong Esther C , van Lier René A W , Gordon Siamon , Hamann Jörg 
Published: September 2022

AbstractThe EGF-TM7 family is a group of class B seven-span transmembrane (TM7) receptors expressed predominantly by cells of the immune system. Family members CD97, EMR1, EMR2, EMR3, and ETL are characterized by an extended extracellular region with a variable number of N-terminal epidermal growth factor (EGF)-like domains coupled to a TM7 domain by a stalk. The EGF domain region of the recently identified EMR2 differs from that of CD97 in only 6 out of 236 amino acids. Although small, this difference has been shown to alter ligand specificity. To analyze the structure and cellular distribution of EMR2, a specific monoclonal antibody (2A1) was generated. Use of 2A1 has demonstrated EMR2, like CD97, to be expressed as a heterodimeric receptor consisting of an extracellular α part and a TM7/cytoplasmic β part. Analysis of EMR2 expression on primary blood leukocytes, on hematopoietic cells lines, and in situ revealed a myeloid-restricted profile. Highest expression levels were detected on the more mature CD16+ blood monocytes, on macrophages, and on BDCA-3+ myeloid DC, whereas little if any expression was found on granulocytes. Unlike CD97, no expression was observed on resting or activated lymphocytes. Different expression patterns and the inability of EMR2 to interact with the CD97 ligand CD55 indicate that the molecular twins EMR2 and CD97 likely have nonredundant functions.
Potentiation by human serum of anti-inflammatory cytokine production by human macrophages in response to apoptotic cells
Authors: Kurosaka Kahori , Watanabe Naoko , Kobayashi Yoshiro 
Published: September 2022

AbstractPhagocytosis of apoptotic cells by macrophages leads to the production of anti-inflammatory cytokines, thereby preventing inflammation. In this study, we demonstrate that human serum potentiates the production of anti-inflammatory cytokines, IL-10 and TGF-β, by PMA-treated THP-1 cells and human monocyte-derived macrophages in response to apoptotic cells, which results in great suppression of the production of proinflammatory cytokine IL-8. Human IgG but not its F(ab)′2 suppressed the IL-8 production. Pretreatment of macrophages but not apoptotic cells with human serum or human IgG caused the suppression, suggesting that immune complex may not be formed with apoptotic cells. When FcγRI was specifically down-modulated by a monoclonal antibody, M22, the potentiating effects of human serum and human IgG on the anti-inflammatory cytokine production and the suppressive effects on IL-8 production were completely abolished. Thus, human IgG and FcγRI appear to be critical in leading to the production of anti-inflammatory cytokines by macrophage in response to apoptotic cells.
Phosphatidylinositol 3-kinase and extracellular signal-regulated kinase are recruited for Fc receptor-mediated phagocytosis during monocyte-to-macrophage differentiation
Authors: García-García Erick , Rosales Ricardo , Rosales Carlos 
Published: September 2022

AbstractThe molecular mechanism involved in Fc receptor-mediated phagocytosis in the different cell types of the immune system is still poorly defined. We investigated the role of phosphatidylinositol 3-kinase (PI 3-K) and extracellular signal-regulated kinase (ERK) in phagocytosis by monocytes and by monocyte-differentiated macrophages. Peripheral blood monocytes and monocytic cells (THP-1 cell line) were able to ingest IgG-coated erythrocytes in the absence of additional stimulus. Phagocytosis by these cells was not blocked by wortmannin and LY294002, specific inhibitors of PI 3-K, or by PD98059, a specific MEK/ERK inhibitor. However, upon differentiation of THP-1 monocytes to macrophages, through treatment with retinoic acid and interferon-γ (IFN-γ), wortmannin and PD98059 blocked Fc receptor-mediated phagocytosis efficiently. Inhibition of phagocytosis by PD98059 was observed after 24 h of IFN-γ treatment, whereas wortmannin could inhibit phagocytosis only after 48 h of IFN-γ treatment. Additionally, phagocytosis of IgG-coated erythrocytes by neutrophils, a more efficient phagocyte, was inhibited by wortmannin and PD98059. Neutrophils and monocyte-differentiated macrophages presented significantly more efficient phagocytosis than monocytes upon PMA stimulation. Taken together, these results indicate that poorly phagocytic leukocytes, such as monocytes, do not require PI 3-K and ERK for phagocytosis. Upon differentiation into macrophages, however, ERK first and PI 3-K second are recruited for regulation of phagocytosis. In addition, our data support the idea that professional phagocytes require ERK and PI 3-K for efficient phagocytosis.
Selective expansion of perforin-positive CD8+ T cells by immature dendritic cells infected with live Bacillus Calmette-Guérin mycobacteria
Authors: Tsunetsugu-Yokota Yasuko , Tamura Hideto , Tachibana Mikiko , Ogata Kiyoyuki , Honda Mitsuo , Takemori Toshitada 
Published: September 2022

AbstractLive, but not dead Bacillus Calmette-Guérin (BCG) is partially protective against infection by Mycobacterium tuberculosis, which causes a disease with high mortality in immune compromised individuals. We have shown that uptake of BCG induces maturation of immature dendritic cells (DCs) regardless of the viability of the bacteria. Importantly, when T cells are cocultured with live BCG-infected DCs, the proportion of CD45RA− perforin+ CD8+ T cells is markedly expanded markedly; however, little expansion is seen when T cells are cocultured with DCs harboring heat-killed BCG. The direct contact of T cells with live BCG-infected DCs was required for the expansion of perforin+ CD8+ T cells. These CD8+ T cells demonstrated a high level of killing activity against BCG-infected macrophages. There was little contribution of cytokines, including IFN-γ, TNF-α, and IL-12, to the expansion of CD8+ T cells by live BCG-infected DCs. We found that the interaction between BCG-infected DCs and CD8+ T cells through CD40/CD40L was crucial for the expansion and maturation of CD8+ T cells, the process of which was CD4-independent. In contrast, blocking the CD58/CD2 but not the CD40/CD40L interaction reduced production of IFN-γ without affecting the maturation of CD8+ T cells. This indicates that the production of IFN-γ and perforin by CD8+ T cells is mediated by distinct signals delivered from BCG-infected DCs. Thus, BCG-specific CD8+ CTL memory cells may be maintained for a long period of time in BCG-vaccinated hosts, and these cells could mature rapidly into effectors through the potent antigen-presenting function of DCs upon mycobacterial infection.
CD137 is expressed by follicular dendritic cells and costimulates B lymphocyte activation in germinal centers
Authors: Pauly Susanne , Broll Karin , Wittmann Margarethe , Giegerich Gerhard , Schwarz Herbert 
Published: September 2022

AbstractCD137, a member of the TNF receptor family, and its ligand are expressed on T lymphocytes and antigen-presenting cells (APC), respectively. During interaction with APC, T lymphocytes receive a potent, costimulatory signal through CD137. Reverse signaling has been demonstrated for the CD137 ligand, which causes activation in monocytes. Here we show that B lymphocytes also receive costimulatory signals through the CD137 ligand. Immobilized CD137 augmented proliferation of preactivated B lymphocytes up to fivefold and immunoglobulin synthesis, up to threefold. CD137 had no effect on resting cells. Further, we show that CD137 is expressed in vivo by follicular dendritic cells (FDC) in germinal centers. Germinal centers form during humoral immune responses and are essential for B lymphocyte affinity maturation. These data imply that, similar to the CD40 receptor/ligand system, which mediates T lymphocyte help to B lymphocytes after the first antigen encounter, the CD137 receptor/ligand system may mediate costimulation of B lymphocytes by FDC during affinity maturation.
Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer's disease
Authors: Griffin W Sue T , Mrak Robert E 
Published: September 2022

AbstractInterleukin-1 (IL-1), a key molecule in systemic immune responses in health and disease, has analogous roles in the brain where it may contribute to neuronal degeneration. Numerous findings suggest that this is the case. For example, IL-1 overexpression in the brain of Alzheimer patients relates directly to the development and progression of the cardinal neuropathological changes of Alzheimer's disease, i.e., the genesis and accumulation of β-amyloid (Aβ) plaques and the formation and accumulation of neurofibrillary tangles in neurons, both of which contribute to neuronal dysfunction and demise. Several genetic studies show that inheritance of a specific IL-1A gene polymorphism increases risk for development of Alzheimer's disease by as much as sixfold. Moreover, this increased risk is associated with earlier age of onset of the disease. Homozygosity for this polymorphism in combination with another in the IL-1B gene further increases risk.
Potent induction of activin A secretion from monocytes and bone marrow stromal fibroblasts by cognate interaction with activated T cells
Authors: Abe Masahiro , Shintani Yasumi , Eto Yuzuru , Harada Kazuyo , Kosaka Masaaki , Matsumoto Toshio 
Published: September 2022

AbstractActivin A is a multifunctional cytokine essential for cell differentiation and apoptosis including erythroid cell differentiation in the bone marrow. In addition, activin A is induced by inflammation and exerts anti-inflammatory effects. However, the mechanism of activin A induction is still unclear, especially by inflammatory processes. Here we show that activin A secretion from monocytes and bone marrow stromal fibroblasts, its major sources in the bone marrow, is markedly enhanced by cognate interaction with activated T cells. This process is mediated by CD40/CD40 ligand interaction as well as concomitantly secreted T cell-derived cytokines, granulocyte macrophage-colony stimulating factor, and interferon-γ. Furthermore, stromal fibroblasts as well as monocytes provide a costimulatory signal to anti-CD3-treated T cells via CD80 and CD86 to maintain the enhanced activin A production. These findings suggest that activin A is potently induced in the bone marrow and may play a role in the suppression of inflammatory or immune processes.
Murine polymorphonuclear neutrophils produce interferon-γ in response to pulmonary infection withNocardia asteroides
Authors: Ellis Terri N , Beaman Blaine L 
Published: September 2022

AbstractNocardia asteroides causes an acute, necrotizing pneumonia characterized by extensive infiltration of polymorphonuclear neutrophils (PMNs) into the lungs. Although PMNs have historically been classified as end-point cells, recent investigations have indicated that PMNs have the ability to secrete cytokines such as interleukin (IL)-4 and IL-12. This study investigated the ability of PMNs to produce cytokines in a murine model of N. asteroides pulmonary infection. Flow cytometric analysis demonstrated the production of interferon-γ (IFN-γ), but not IL-4, by PMNs in response to this infection. IFN-γ production correlated with peak infiltration of PMNs into the lungs. Cell sorting and enzyme-linked immunosorbent assay were used to confirm cytokine production by cells with nuclear morphology characteristic of PMNs. This is the first report of IFN-γ production by neutrophils in response to an infection in vivo. These results suggest that PMNs play an important role in directing the host toward a T helper cell type 1 phenotypic response in the lungs.
Macrophages in gene therapy: cellular delivery vehicles and in vivo targets
Authors: Burke B , Sumner S , Maitland N , Lewis C E 
Published: September 2022

AbstractThe appearance and activation of macrophages are thought to be rapid events in the development of many pathological lesions, including malignant tumors, atherosclerotic plaques, and arthritic joints. This has prompted recent attempts to use macrophages as novel cellular vehicles for gene therapy, in which macrophages are genetically modified ex vivo and then reintroduced into the body with the hope that a proportion will then home to the diseased site. Here, we critically review the efficacy of various gene transfer methods (viral, bacterial, protozoan, and various chemical and physical methods in transfecting macrophages in vitro, and the results obtained when transfected macrophages are used as gene delivery vehicles. Finally, we discuss the use of various viral and nonviral methods to transfer genes to macrophages in vivo. As will be seen, definitive evidence for the use of macrophages as gene transfer vehicles has yet to be provided and awaits detailed trafficking studies in vivo. Moreover, although methods for transfecting macrophages have improved considerably in efficiency in recent years, targeting of gene transfer specifically to macrophages in vivo remains a problem. However, possible solutions to this include placing transgenes under the control of macrophage-specific promoters to limit expression to macrophages or stably transfecting CD34+ precursors of monocytes/macrophages and then differentiating these cells into monocytes/macrophages ex vivo. The latter approach could conceivably lead to the bone marrow precursor cells of patients with inherited genetic disorders being permanently fortified or even replaced with genetically modified cells.
Molecular mechanisms of platelet-mediated leukocyte recruitment during myocardial reperfusion
Authors: Kupatt Christian , Wichels Reinhard , Horstkotte Jan , Krombach Fritz , Habazettl Helmut , Boekstegers Peter 
Published: September 2022

AbstractLeukocyte interaction with platelets and endothelial cells as cause of myocardial stunning was investigated. Mice were anesthetized and, after thoracotomy, the LAD was ligated for 20 min. Where indicated, rhodamine 6G for leukocyte labeling, fluorescence-labeled platelets, and the GPIIb/IIIa antagonist Tirofiban wer infused at the onset of reperfusion in vivo. After 15 min, hearts were quickly excised and analyzed by fluorescence microscopy or assessed for left ventricular developed pressure (LVDP). After in vivo ischemia and reperfusion, leukocyte retention in the heart was 55 ± 5/field in wild-type hearts, 38 ± 3/field in P-selectin−/− hearts, and 23 ± 4/field in P-selectin/intercellular adhesion molecule-1 (ICAM-1)−/− hearts. Postischemic LVDP (48±4 mmHg in wild-type hearts) improved in P-selectin−/− and P-selectin/ICAM-1−/− hearts (58±4 and 79±6 mmHg). Tirofiban reduced platelet adhesion (23±4/field vs. 61±2/field in wild-type hearts) and leukocyte recruitment (34±2/field), improving LVDP (63±4 mmHg). Whereas wild-type platelets displayed similar adherence to P-selectin/ICAM-1−/− hearts as platelets from the same genetic strain (63±3 vs. 61±4 platelets/field), wild-type platelet infusion restored postischemic leukocyte recruitment in P-selectin/ICAM-1−/− hearts (55±4/field vs. 23±4/field), an effect sensitive to Tirofiban inhibition (23±4 leukocytes/field, 22±3 platelets/field). We conclude that platelets contribute postischemic leukocyte adhesion in the heart via P-selectin and GPIIb/IIIa.
The role of ceramide of human macrophage gangliosides in activation of human macrophages
Authors: Berenson Charles S , Gallery Melissa A , Smigiera Jane M , Rasp Robin H 
Published: September 2022

AbstractGangliosides of macrophages have immunoregulatory and structural attributes, distinct from neural gangliosides. We previously produced a monoclonal antibody to human macrophage gangliosides (HMG; mAb25F4), which inhibited macrophage migration and recognized a surface-accessible epitope. We investigated expanded immunoregulatory properties and molecular domains for antibody recognition. mAb25F4 directly induced human macrophage production of proinflammatory cytokines, interleukin-1β, and tumor necrosis factor α. Conditions were established for selective, reversible depletion of HMG with D-threo-(R, R)-1-phenyl-2-decanoyl-amino-3-morpholine-1-propa-nol. mAb25F4 had diminished recognition for ganglioside-depleted macrophages, which was restored with regeneration of gangliosides. Although desialylation of HMG did not impair mAb25F4 recognition, enzymatic cleavage of ceramide abolished antibody binding. Antibody recognition was specific for the ceramide fraction, with preferential recognition or ceramide of HMG and murine macrophage gangliosides and limited recognition for neural tissue ceramide and gangliosides. This study underscores the importance of structurally distinct ceramide of macrophage gangliosides as a critical domain for ganglioside-mediated activation of human macrophages.
Disruption of CD40/CD40 ligand interaction with cleavage of CD40 on human gingival fibroblasts by human leukocyte elastase resulting in down-regulation of chemokine production
Authors: Nemoto Eiji , Tada Hiroyuki , Shimauchi Hidetoshi 
Published: September 2022

AbstractCD40 is a crucial element in the process of fibroblast activation. We demonstrated that treatment of human gingival fibroblast (HGF) with human leukocyte elastase (HLE), a neutrophil serine protease, down-regulated the expression of CD40 and binding to the CD40 ligand (CD40L) using flow cytometry. The other neutrophil serine proteases, cathepsin G and proteinase 3, exhibited markedly less activity for CD40 reduction. The CD40 reduction by HLE was also observed in skin and lung fibroblasts, but not in monocytes, macrophages, and dendritic cells. The reduction resulted from direct proteolysis by HLE on the cell surface, because HLE reduced CD40 on fixed HGF and also on cell lysates and membranes. HLE treatment of HGF decreases interleukin (IL)-8 and macrophage chemoattractant protein-1 production by HGF when stimulated by CD40L, but not by IL-1α, suggesting that HLE inhibited a CD40-dependent cell activation. These results suggest that HLE possesses an anti-inflammatory effect for the HGF-mediated inflammatory process.
Effects of catecholamines on kinase activation in lung neutrophils after hemorrhage or endotoxemia
Authors: Arcaroli John , Yang Kuang-Yao , Yum Ho-Kee , Kupfner John , Pitts Todd M , Park Jong Sung , Strassheim Derek , Abraham Edward 
Published: September 2022

AbstractCatecholamines are released in high levels after hemorrhage or endotoxemia and have been shown to modulate immune function, including cellular release of inflammatory mediators. In the present experiments, we examined the effects of endogenous and exogenous catecholamines on neutrophil accumulation and activation in the lungs using pretreatment with α- or β-antagonists or α-adrenergic agonists before hemorrhage or endotoxemia. These studies showed that α-, but not β-adrenergic stimuli, modulated the severity of acute lung injury after hemorrhage or endotoxemia, and α-adrenergic stimuli was proinflammatory after hemorrhage but anti-inflammatory after endotoxemia. The observed α-adrenergic effects on lung neutrophil activation appeared to involve primarily the extracellular signal-regulated kinase pathway at the upstream kinase Raf, but not Ras. Although p38 and protein kinase A were activated in lung neutrophils after hemorrhage or endotoxemia, these kinases were not affected by α- or β-adrenergic modulation. These results demonstrate that catecholamines have important immunomodulatory effects in vivo that affect intracellular signaling pathways in neutrophils and neutrophil-driven, inflammatory processes such as the development of acute lung injury.
Platelet factor 4 induces human natural killer cells to synthesize and release interleukin-8
Authors: Martí Francesc , Bertran Esther , Llucià Montserrat , Villén Esther , Peiró Matilde , Garcia Joan , Rueda Fèlix 
Published: September 2022

AbstractWe provide evidence that platelet factor 4 (PF4), but not the related chemokine neutrophil-activating polypeptide-2, induced highly purified human natural killer (NK) cells to produce interleukin (IL)-8 in a time- and dosage-dependent manner. This ability was retained even while PF4 was bound to heparin. PF4 increased the steady state level of IL-8 mRNA, likely implying a transcriptional effect of PF4. Stimulation of NK cells through the Fc receptor for immunoglobulin G-IIIA was foud to synergistically increase the effect of PF4 on IL-8 production but did not affect IL-2-related activities such as cytotoxic activity and proliferation. Pertussis toxin did not block the PF4-derived IL-8 production in NK cells, but this response was sensitive to wortmannin, implicating a role of phosphatidylinositol 3-kinase in the intracellular signaling pathway triggered by PF4. Our results characterize a new capacity for PF4 and provide further evidence for the pivotal role of NK cells in the environment of inflammation.
High circulating levels of the IL-1 type II decoy receptor in critically ill patients with sepsis: association of high decoy receptor levels with glucocorticoid administration
Authors: Müller Beat , Peri Giuseppe , Doni Andrea , Perruchoud André P , Landmann Regine , Pasqualini Fabio , Mantovani Alberto 
Published: September 2022

AbstractThe objective of this study was to evaluate whether the interleukin (IL)-1 decoy receptor (R), a negative pathway of regulation of IL-1, is correlated with severity of infection in critically ill patients and reflects the activation of anti-inflammatory pathways by glucocorticoid hormones. Plasma samples were obtained from 101 consecutive, critically ill patients admitted to the intensive care unit with different severities of microbial infection, as defined by standardized criteria. Here, we report that the IL-1 type II decoy R(II) is elevated in critically ill patients, especially in severe, systemic infection and culture-positive infections. In patients with a marked systemic inflammatory response syndrome 4, a pronounced, sepsis-induced further increase of circulating IL-1 decoy RII levels was evident. Thirty-six patients treated with glucocorticoid hormones had significantly higher levels of IL-1 decoy RII, but lower IL-6 and C-reactive protein, than 67 untreated subjects. The usefulness of IL-1RII, in particular as a potential marker for the activation of anti-inflammatory pathways or for responsiveness to anti-inflammatory agents such as glucocorticoid hormones, deserves further analysis.