bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shape and shift changes related to the function of leukocyte integrins LFA-1 and Mac-1
Authors: Hogg Nancy , Leitinger Birgit 
Published: September 2022

AbstractIntegrin activity on leukocytes is controlled tightly, ensuring that ligand binding occurs only when leukocytes are in contact with their targets. For an integrinlike LFA-1, this ligand-binding activity comes about as a result of increased integrin clustering. Affinity regulation of integrins also plays a role, but the conformational changes giving rise to increased affinity appear to be secondary to clustering. Conformationally altered LFA-1 can be created artificially by deletion of the I domain, which is the key domain involved in ligand binding for many but not all integrins. Although I domain-deleted LFA-1 (ΔI-LFA-1) cannot bind ligand, it is able to signal constitutively into the cell. One measure of this signaling activity is the ability of ΔI-LFA-1 to activate β1 integrins on the same T lymphocyte. Leukocytes use LFA-1 to migrate across the endothelium. Active β1 integrins may be required subsequently to bind the matrix proteins encountered by leukocytes as they continue their voyage into the tissue interior.
Expression, tissue distribution, and cellular localization of the antiapoptotic TIP-B1 protein
Authors: Berleth Erica S , Masso-Welch Patricia A , Kazim Latif A , Ip Margot M , Mihich Enrico , Ehrke M Jane 
Published: September 2022

AbstractTIP-B1 is a novel 27-kDa protein isolated from the cytosol of tumornecrosis factor (TNF)-stimulated cells. Cells preincubated with TIP-B1are protected from TNF-induced apoptosis. This study showed that, aswith normal fibroblasts and U937 histiocytic lymphoma, human MCF7mammary adenocarcinoma cells were protected from TNF in aconcentration-dependent manner by pretreatment with either TNF orpurified TIP-B1. Immunoblot and immunohistochemical analyses indicatedexpression of both TIP-B1 mRNA and protein in MCF7 cells and heart, kidney, brain, liver, ovary, uterus, thymus, spleen, lymph node, andmammary gland cells throughout their development. Expression of TIP-B1was heterogeneous, with staining of specific cell types within tissues. Based on the ability of TIP-B1 to protect both normal and tumor cellsfrom TNF-induced apoptosis and its broad tissue distribution, withexpression only in select cells within those tissues, a role for TIP-B1in the regulation of TNF-induced effects is strongly indicated.
Immunocytochemical localization of peptidylarginine deiminase in human eosinophils and neutrophils
Authors: Asaga Hiroaki , Nakashima Katsuhiko , Senshu Tatsuo , Ishigami Akihito , Yamada Michiyuki 
Published: September 2022

AbstractPeptidylarginine deiminase, registered as PAD V in the DDBJ/GenBank/EMBL data banks, is expressed in HL-60 cells differentiated into granulocytes or monocytes. We analyzed PAD activities in density-fractionated human peripheral blood cell fractions. PAD activity with similar substrate specificity to that of PAD V was found in the eosinophil and neutrophil fractions, which showed single bands comigrating with authentic PAD V on immunoblotting with an anti-PAD V antibody. Both the biochemical and immunoblotting analyses showed marked enrichment of PAD V in the eosinophil fraction. Its immunoreactivity appeared to localize in eosinophilic granules at high density and in myeloperoxidase-negative cytoplasmic granules of neutrophils at low density, as determined by confocal laser-scanning microscopy. Possible roles of PAD V in myeloid differentiation and granulocyte function are discussed. In addition, we present evidence for the presence of PAD(s) that are antigenically different from PAD V in monocytes and lymphocytes.
Biliary glycoprotein (BGPa, CD66a, CEACAM1) mediates inhibitory signals
Authors: Chen Tie , Zimmermann Wolfgang , Parker James , Chen Ines , Maeda Akito , Bolland Silvia 
Published: September 2022

AbstractBiliary glycoprotein (BGP, CD66a, CEACAM1) is a member of the carcinoembryonic antigen family (CEA, CD66), a group of transmembrane proteins belonging to the immunoglobulin superfamily. The structural features surrounding the tyrosine residues in the cytoplasmic domain of BGP share similarity with the consensus sequence of the immunoreceptor tyrosine-based inhibition motif (ITIM), the docking site for SHIP, SHP-1, and SHP-2 molecules. Using the well-characterized inhibitory receptor, FcγRIIB, we constructed a FcγRIIB-BGPa chimeric molecule that contained the extracellular and transmembrane domain of FcγRIIB and the cytoplasmic tail of BGPa and expressed it in DT40 B cells. Our results showed that FcγRIIB-BGPa, just like the unmodified FcγRIIB molecule, inhibited calcium influx in activated DT40 B cells. Substitution of tyrosine with phenylalanine (Y459F) in FcγRIIB-BGPa completely abrogated its ability to inhibit calcium influx, indicating that the motif surrounding Y459 is ITIM. The presence of ITIM was also supported by showing that the FcγRIIB-BGPa-mediated inhibitory effect was reduced in SHP-1and SHP-2 mutant DT40 B cells and further diminished in a SHP-1/-2 double-deficient mutant line. The results suggest that SHP-1 and SHP-2 are required for the FcγRIIB-BGPa-mediated inhibitory signals.
Regulation of hematopoiesis by gap junction-mediated intercellular communication
Authors: Montecino-Rodriguez Encarnacion , Dorshkind Kenneth 
Published: September 2022

AbstractGap junctions are intercellular channels formed by individual structural units known as connexins (Cx) that allow the intercellular exchange of small molecules between cells. The presence of Cx protein in bone marrow and thymic stromal cells and the demonstration that these cells are functionally coupled have led to the hypothesis that groups of stromal cells in the bone marrow and thymus form a functional syncytium through which their hematopoietic support capacity is coordinated. The validity of this hypothesis was recently tested in a newly developed strain of mice in which the gene encoding Cx43, the principal Cx expressed in hematopoietic tissues, was disrupted. Studies of myelopoiesis and lymphopoiesis in these Cx43-deficient mice revealed that expression of Cx43 in the bone marrow and thymus is critically important during periods of active hematopoiesis, such as during embryogenesis and after recovery from cytoablative treatments. The clinical implications of these observations, as well as issues that remain to be addressed to understand the mechanism(s) by which gap junctions regulate hematopoiesis, are addressed.
Activation of human neutrophils in vitro and dieldrin-induced neutrophilic inflammation in vivo
Authors: Pelletier Martin , Roberge Charles J , Gauthier Marc , Vandal Karen , Tessier Philippe A , Girard Denis 
Published: September 2022

AbstractMany chemicals of environmental concern are known to alter the immune system and are considered toxic molecules because they affect immune cell functions. Inflammation related to environmental chemical exposure, however, is poorly documented, except that from air pollutants. In this study, we found that the organochlorine insecticide dieldrin could not alter the ability of human neutrophils to phagocytose opsonized sheep red blood cells at nonnecrotic concentrations (0.1, 1, 10, and 50 μM). However, dieldrin was found to increase human neutrophil superoxide production, RNA synthesis, and proinflammatory cytokine interleukin-8 production. The normal apoptotic rate of neutrophils evaluated by both cytology and flow cytometry (CD-16 staining) was not altered by dieldrin treatments, and this was correlated with its inability to inhibit spreading of neutrophils onto glass. Using the murine air pouch model, we found that dieldrin induces a neutrophilic inflammation. Taken together, these results demonstrated that dieldrin is a proinflammatory contaminant. To our knowledge, this is the first report establishing that dieldrin is a contaminant exhibiting proinflammatory properties. In addition, it is the first time that the murine air pouch model has been successfully used to confirm that a chemical of environmental concern can induce an inflammatory response in vivo.
Proinflammatory activity of glycosylphosphatidylinositol anchors derived fromTrypanosoma cruzi: structural and functional analyses
Authors: Almeida Igor C , Gazzinelli Ricardo T 
Published: September 2022

AbstractA strong activation of macrophages is observed during acute infection with Trypanosoma cruzi. Little is known, however, about the parasite molecules that are responsible for this early activation of innate immunity. Recent studies have shown the stimulatory activity of protozoan-derived glycosylphosphatidylinositol (GPI) anchors on cultured macrophages. In this review, we provide a detailed analysis of the correlation between structure and proinflammatory activity byT. cruzi-derived GPI anchors. We also cover the studies that have identified the Toll-like receptor 2 as a functional GPI receptor and have partially characterized signaling pathways triggered by T. cruzi-derived GPI anchors, which lead to the synthesis of proinflammatory cytokines in macrophages. Finally, we discuss the implications of these findings in resistance and pathogenesis during the infection with T. cruzi.
Leukocytes infiltrating the pancreatic islets of nonobese diabetic mice are transformed into inactive exiles by combinational anti-cell adhesion therapy
Authors: Kommajosyula Sharada , Reddy Shiva , Nitschke Kristina , Kanwar Jagat R , Karanam Muralidhar , Krissansen Geoffrey W 
Published: September 2022

AbstractLeukocytes infiltrate the pancreatic islets of nonobese diabetic mice, causing β-cell destruction and autoimmune Type I diabetes. Here, wecompletely blocked adoptive transfer of diabetes and reducedspontaneous disease incidence from 71% to 17% by simultaneouslyadministering a combination of antibodies directed against α4, β2,and β7 integrins and their ligands VCAM-1, MAdCAM-1, and ICAM-1 for52 and 28 days, respectively. CD4 and CD8 T cells and macrophages wereexcluded from islets and remained entrapped in a peri-islet location asinactive exiles, no longer expressing normal levels of interferon-γ,interleukin-4, and iNOS. Only IL-10 expression was retained, whichcould aid immunosuppression. Infiltrating leukocytes retained aperi-islet location, even 215 days following suspension of antibodytreatment, potentially forming a barrier to the entry of active, autoantigen-reactive T cells. Combination treatment was effectiveagainst spontaneous disease when administered from 7 days of age butineffective when initiated late in the prediabetic period (day 40 or70). Nevertheless, anti-α4 subunit mAb monotherapy alone was veryeffective, reducing insulitis to levels similar to those obtained withcombinational antibody treatment, suggesting that α4 integrins aremajor receptors contributing to leukocyte infiltration. Treatment withanti-α4 integrin antibody retained some therapeutic benefit whenadministered from days 7, 40, or 70 of age. The results haveimplications for the treatment of diabetes and provide a unique insightinto the fate of disease-forming leukocytes following anti-CAMtherapy.
Membrane trafficking of CD1c on activated T cells
Authors: Salamone María del C , Mendiguren Ana Karina , Salamone Gabriela V , Fainboim Leonardo 
Published: September 2022

AbstractWe investigated the regulation of and the intracellular traffickinginvolved in the membrane expression of CD1c antigen on activated matureT cells. Membrane expression of this glycoprotein was highly regulatedand dependent on the activation state of the cells. The presence of the CD1c antigen on activated peripheral blood mononuclear cells (PBMCs)was confirmed by flow cytometry, reverse transcriptase-PCR (RT-PCR),and immunoperoxidase staining. The RT-PCR analysis of the α3- and3′-untranslated regions of CD1C showed thatphytohemagglutinin (PHA) activation induced expression of transcriptsthat encode the three isoforms (soluble, membrane, andcytoplasmic/soluble). Immunocytochemical studies showed a specificassociation of CD1c with the cell membrane and a cytoplasmic, perinuclear distribution. Although flow-cytometric staining confirmedthe intracellular presence of CD1c, membrane expression on PHA blastcells was not detected. We found that membrane detection of CD1cantigen was temperature dependent. Cell surface binding of theanti-CD1c monoclonal antibody (mAb) was consistently negative at 4 and37°C but was detected at room temperature (18–22°C). Atphysiologic temperatures, activated PBMCs showed intracellularaccumulation of the anti-CD1c mAbs, indicating that CD1c cycled betweencell surface and intracellular compartments. The CD1c exocytosispathway was sensitive to Brefeldin A, cytochalasin B, andchloroquine.
Phosphatidylinositol 3-kinase and ERK are required for NF-κB activation but not for phagocytosis
Authors: García-García Erick , Sánchez-Mejorada Gabriela , Rosales Carlos 
Published: September 2022

AbstractThe molecular events that transduce signals from Fc receptors to the various cellular responses are still poorly defined. We have investigated the role of phosphatidylinositol 3-kinase (PI 3-K) and extracellular signal-regulated kinase (ERK) in gene activation and phagocytosis in monocytes. In the THP-1 monocytic cell line, cross-linking of Fc receptors by immune complexes results in activation of the transcription factor NF-κB, via activation of ERK. Activation of both ERK and NF-κB was blocked by wortmannin and LY294002, specific inhibitors of PI 3-K. Wortmannin also inhibited the Fc receptor-mediated increase in the cytosolic calcium concentration, but it did not block immunoglobulin G (IgG)-mediated phagocytosis. In addition, the ERK inhibitor PD98059 did not block phagocytosis of IgG-coated erythrocytes. Both the increase in the cytosolic calcium concentration and phagocytosis depend on an active actin cytoskeleton, as indicated by the total lack of both responses after treatment with cytochalasin B. In contrast, cytochalasin B did not affect Fc receptor-mediated activation of NF-κB. These results identify PI 3-K and ERK as important signaling molecules in the Fc receptor signal transduction pathway of monocytes, which leads to the nucleus for gene activation. These results also suggest that, in contrast to other cell types, unstimulated monocytes do not require PI 3-K and ERK for phagocytosis.
Crystal-induced neutrophil activation. VII. Involvement of Syk in the responses to monosodium urate crystals
Authors: Desaulniers Philippe , Fernandes Maria , Gilbert Caroline , Bourgoin Sylvain G , Naccache Paul H 
Published: September 2022

AbstractThe inflammatory response in acute gouty arthritis is in large part a result of the interaction between neutrophils and monosodium urate (MSU) crystals. The tyrosine kinase Syk, which has been largely associated with the phagocytic response by Fc receptors and with spreading mediated by integrins, has been identified as one of the major proteins tyrosine-phosphorylated in human neutrophils upon stimulation by MSU crystals and is known to be mediated in part by the Fc receptor, CD16. This has led to the present examination of the implication of Syk in the activation pathways used by MSU crystals. The tyrosine-phosphorylation patterns induced by MSU crystals and by the ligation of CD16 were inhibited by piceatannol, which, conversely, only slightly delayed but did not diminish the peak of tyrosine phosphorylation induced by cross-linking CD32 or by the addition of fMet-Leu-Phe. Moreover, piceatannol inhibited the activity of Syk as monitored by in vitro kinase assays, by its in situ tyrosine phosphorylation, and by its activity toward exogenous substrates after stimulation by MSU crystals. We also measured the impact of piceatannol on the mobilization of calcium, the production of superoxide anions, and the activity of PLD stimulated by MSU crystals. We noted a distinct inhibition of all these responses by piceatannol. Finally, the morphological changes observed in neutrophils as characteristic of MSU crystal internalization were diminished significantly by piceatannol. The results obtained show that Syk plays a critical and central role in the signal-transduction pathways called upon by MSU crystals subsequent to their interaction with human neutrophils.
The role of CD44 during CD40 ligand-induced dendritic cell clustering and maturation
Authors: Termeer Christian , Johannsen Henning , Braun Thorsten , Renkl Andreas , Ahrens Thomas , Denfeld Ralph W , Lappin Mike B , Weiss Johannes M , Simon Jan C 
Published: September 2022

AbstractThe interaction between CD40 on dendritic cells (DC) and its ligand CD154 has been recognized to be an important feature in the maturation of DC. Here, we were interested in the role of CD44 a surface receptor shown to mediate cell-cell adhesion and binding to Hyaluronic acid (HA). Western blot analysis of human DC stimulated for 3–12 h with CD154 revealed the rapid induction of the 85 kDa standard form of CD44 and an increased HA-binding affinity. Time-lapse video-imaging microscopy of human DC co-cultured on CD154-transfected murine fibroblasts showed that the CD44 up-regulation coincided with the rapid induction of homotypic DC clustering, which did not occur on empty vector-transfected fibroblasts. In this system, addition of anti-CD44s mAbs abrogated DC-cluster formation, thereby inhibiting further maturation, as shown by a reduced TNF-α production and inhibition of CD154-induced MHC class II up-regulation. However, co-incubation with HA-degrading enzymes induced no changes in the CD154-mediated DC clustering and maturation.
Treatment of multiple sclerosis patients with interferon-β primes monocyte-derived macrophages for apoptotic cell death
Authors: Van Weyenbergh Johan , Wietzerbin Juana , Rouillard Dany , Barral-Netto Manoel , Liblau Roland 
Published: September 2022

AbstractAlthough interferon (IFN)-β has shown a significant clinical benefit in multiple sclerosis (MS), its mechanism of action remains unclear. We found that IFN-β treatment of patients with MS resulted in a significant increase in apoptotic cell death (measured by annexin V staining and nuclear fragmentation) of monocyte-derived macrophages, as compared with cells derived from patients before treatment. Stimulation of the cells with IFN-β in vitro resulted in an even further increase of annexin V binding, as well as increased Fas (CD 95, APO-1) expression. However, no increased Fas expression, apoptotic monocytes, or monocytopenia were observed upon in vivo treatment. This indicates that IFN-β does not deliver a death signal to monocytes but rather primes for subsequent macrophage apoptosis upon activation or differentiation.
Regulation of the very late antigen-4-mediated adhesive activity of normal and nonreleaser basophils: roles for Src, Syk, and phosphatidylinositol 3-kinase
Authors: Andrews Ronald P , Kepley Christopher L , Youssef Lama , Wilson Bridget S , Oliver Janet M 
Published: September 2022

AbstractNormal human basophils express the integrin, VLA-4, and cross-linking their high-affinity IgE receptor, FcɛRI, increases their VLA-4-dependent adhesion to VCAM-1-transfected Chinese hamster ovary (CHO) cells. Here we show that the FcɛRI-mediated up-regulation of normal basophil VLA-4 adhesion is abolished by the Src inhibitor, PP1, the Syk inhibitor, ER-27319, and the phosphatidylinositol 3-kinase inhibitor, wortmannin. PP1, but not ER-27319 or wortmannin, also reduces basal adhesion and adhesion stimulated by chemotactic peptide, by Ca++ ionophores, and by phorbol myristate acetate (PMA). Nonreleaser basophils (the consistently Syk-deficient, variably Lyn-deficient, severely degranulation-impaired cells found in about 10% of donors) share the PP1 phenotype of lowered basal adhesion, no FcɛRI-mediated adhesion up-regulation, and reduced adhesive responses to chemoattractant ionophores and PMA. These results implicate Src kinases in the control of basal VLA-4 activity and place Syk and phosphatidylinositol 3-kinase in the pathway linking FcɛRI cross-linking to VLA-4 up-regulation. Both Src and Syk-regulated components of adhesion may be impaired in nonreleaser basophils.
Modes of action of Freund's adjuvants in experimental models of autoimmune diseases
Authors: Billiau Alfons , Matthys Patrick 
Published: September 2022

AbstractFreund's adjuvants are irreplaceable components of induction protocols of many experimental animal models of autoimmune disease. Apart from the early studies done in the 1950s and 1960s, no further direct investigation on the mode of action of these adjuvants has been undertaken. It is generally assumed that incomplete (IFA) and complete Freund's adjuvant (CFA) act by prolonging the lifetime of injected autoantigen, by stimulating its effective delivery to the immune system and by providing a complex set of signals to the innate compartment of the immune system, resulting in altered leukocyte proliferation and differentiation. Here, we review evidence collected from various types of studies that provide more insight in the specific alterations of the immune response caused by IFA and CFA. Early events include rapid uptake of adjuvant components by dendritic cells, enhanced phagocytosis, secretion of cytokines by mononuclear phagocytes, and transient activation and proliferation of CD4+ lymphocytes. The mycobacterial components within CFA signal T lymphocytes to assume a Th1 profile so that strong delayed-type hypersensitivity against autoantigens develops. In the absence of mycobacteria, T-lymphocyte differentiation tends to assume a Th2 profile with strong antibody production only. The mycobacterial component also accounts for a morphologic and functional remodeling of the haemopoietic system that develops over a period of several weeks and that is characterized by a drastic expansion of Mac-1+ immature myeloid cells. These cells have been found to be associated with enhanced disease in some models but with reduced disease in others. Thus, in experimental autoimmune diseases, CFA-mediated activation of the innate immune compartment is important not only by regulating the early induction phase but also by providing a surplus of effector and regulator cells in the late phase.
Induction of syngeneic graft-versus-host disease in LPS hyporesponsive C3H/HeJ mice
Authors: Flanagan Diana Lowery , Gross Rachel , Jennings C Darrell , Caywood Betty E , Goes Sarah , Kaplan Alan M , Bryson J Scott 
Published: September 2022

AbstractSyngeneic GVHD (SGVHD) develops following syngeneic bone marrow transplantation and treatment with cyclosporine A. Previous studies have demonstrated a role for IL-12, IFN-γ, and TNF-α in the development of murine SGVHD. Macrophages can be activated to secrete IL-12 and TNF-α via a T-cell-dependent or T-cell-independent pathway (LPS or bacterial products). Studies were designed to determine if LPS participated in the development of SGVHD in C3H/HeN (LPS-responsive) and C3H/HeJ (LPS-hyporesponsive) mice. C3H/HeJ and C3H/HeN mice had similar levels of disease induction and pathology. Following induction of SGVHD, treatment of C3H/HeN, but not C3H/HeJ, mice with a sublethal dose of LPS resulted in mortality. However, neutralization of IL-12 abrogated the development of disease in C3H/HeJ mice, demonstrating that activated macrophages and their products participated in the development of SGVHD in these animals. These data suggested that LPS responsiveness was not a predisposing factor for SGVHD induction.