bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of H2 histamine receptor-mediated cAMP generation and granulocytic differentiation by extracellular nucleotides via activation of protein kinase C
Authors: Suh Byung-Chang , Lee Hyosang , Lee Ihn-Soon , Kim Kyong-Tai 
Published: September 2022

AbstractExtracellular ATP exerts a variety of biological actions through several kinds of P2 receptor in HL-60 promyelocytes. We show that stimulation of P2Y2 receptors with ATP and analogs resulted in the inhibition of a subsequently histamine-induced cAMP production and functional differentiation. Treatment of the cells with phorbol 12-myristate 13-acetate also blocked the histamine-mediated cAMP generation just as ATP did. Incubation of the cells with the protein kinase C inhibitor bisindolylmaleimide (GF109203X) abolished the inhibitory effects of extracellular nucleotides, suggesting that protein kinase C may act as an inter-regulator between two receptors. However, ATP did not affect the binding affinity or total binding of [3H]histamine to membrane receptors; it also did not heterologously desensitize H2 receptors. The ATP treatment synergistically elevated the cAMP levels induced directly by forskolin or indirectly by G protein activation after cholera toxin treatment. This indicates that the site of the protein kinase C action is not the G protein or effector enzyme. Co-stimulation of the cells with nucleotides and histamine inhibited histamine-mediated granulocytic differentiation, which was evaluated by looking at the extent of N-formyl-methionyl-leucyl-phenylalanine responses. Taken together, the results demonstrate that extracellular nucleotides are negatively involved in the modulation of histamine signaling via activation of protein kinase C, probably by inhibiting coupling between receptor and G protein.
MAP kinase activation in macrophages
Authors: Rao K Murali Krishna 
Published: September 2022

AbstractStimulation of macrophages by a variety of agents causes activation of mitogen-activated protein kinases (MAPKs). Activation of MAPKs by lipopolysaccharide involves CD14 and Toll receptors. Subsequent steps still remain to be explored. Tumor necrosis factor-α (TNF-α)-induced activation of MAPKs has been shown to involve the death domain proteins (TRADD, FADD, MADD) and TRAFs. Other molecules involved in this pathway include the protein kinases, ASK1, germinal center kinase (GCK), hematopoietic progenitor kinase 1 (HPK1), and GCK-related kinase (GCKR). Although, these pathways have been described in various cell types, their role in macrophages remains to be established. The availability of knockout mice and constitutively active and dominant-negative mutants of MAPKs should greatly enhance our understanding of this field. The activation of MAPKs seems to be different in cell lines compared with primary cells. Among the macrophages, cells from different compartments show different expression of receptors and signal transduction molecules. These differences may account for differences in MAPK activation and other phenotypic differences in macrophages from different compartments. Therefore, it is important to use primary cells for studying MAPK signal-transduction pathways, and the data from cell lines should not be extrapolated to primary cells.
Iron transport intoMycobacterium avium-containing phagosomes from anNramp1Gly169-transfected RAW264.7 macrophage cell line
Authors: Kuhn Donald E , Lafuse William P , Zwilling Bruce S 
Published: September 2022

AbstractNramp1 is an important determinant of innate resistance of macrophages to the growth of intracellular microorganisms. We previously showed that Nramp1 functions to transport iron from the cytoplasm into phagosomes of Mycobacterium avium-infected macrophages. The purpose of this investigation was to further characterize the factors that regulate Nramp1-mediated iron transport into phagosomes. Treatment of Nramp1Gly169 macrophages with the lysomotrophic agents chloroquine or ammonium chloride reduced the import of iron significantly. We found that macrophage-activating cytokines, including TNF-α, IFN-γ, IL-1α, and GM-CSF, when added prior to M. avium, increased the transport of iron into the phagosome. This increase in iron transport was not a result of an increased amount of Nramp1 protein in the phagosome nor to new protein synthesis. Treatment of Nramp1Gly169-transfected macrophages with inhibitors of protein kinase C (PKC) diminished the import of iron into the phagosomes. Iron import was inhibited by an anti-Nramp1 antibody against the putative fourth outer-loop region of Nramp1 but not by an anti-Nramp1 antibody against the carboxy terminus. The significance of these results on the orientation of Nramp1 in the phagosome membrane and on the transport of iron is discussed.
CpG DNA increases primary malignant B cell expression of costimulatory molecules and target antigens
Authors: Jahrsdörfer Bernd , Hartmann Gunther , Racila Emil , Jackson Wallen , Mühlenhoff Lars , Meinhardt Gerold , Endres Stefan , Link Brian K , Krieg Arthur M , Weiner George J 
Published: September 2022

AbstractMultiple factors, including expression of costimulatory molecules, antigen-presenting molecules, and target antigens, likely impact the efficacy of antibody therapy and other approaches to the immunotherapy of B cell malignancy. Unmethylated CpG-dinucleotides in select base contexts (“CpG motifs”) that resemble sequences found in bacterial DNA are potent immunostimulatory agents capable of inducing a complex immune response, including a strong B cell stimulus. We examined the effect of a potent human CpG oligonucleotide (CpG ODN 2006) on different types of primary human malignant B cells and reactive follicular hyperplasia. CpG oligodeoxynucleotide (CpG ODN), but not control (non-CpG ODN), increased the expression of costimulatory molecules (CD40, CD80, CD86, CD54) on malignant B cells without altering the phenotype of B cells obtained from reactive follicular hyperplasia. CpG ODN also enhanced expression of class I and class II MHC in most samples. CD20 expression was increased in response to CpG ODN, most notably in B-CLL and marginal zone lymphoma. An inverse correlation was found between baseline expression of CD20 and CD40 and their expression after exposure to CpG ODN, thus the most significant increase in expression of these molecules was found in those samples that had the lowest baseline levels. In conclusion, CpG ODN can lead to increasing expression of molecules involved in costimulation, antigen presentation, and as targets for antibody-based therapy and deserve further evaluation as potential immunotherapeutic agents for B cell malignancy.
Proteinase 3, Wegener's autoantigen: from gene to antigen
Authors: van der Geld Y M , Limburg P C , Kallenberg C G M 
Published: September 2022

AbstractProteinase 3 (PR3) is one of four serine protease homologues in the azurophilic granules of neutrophils and granules of monocytes. It is of importance that anti-neutrophil cytoplasmic antibodies (ANCA) in patients with Wegener's granulomatosis (WG) are mainly directed against PR3 only. Furthermore, PR3 is overexpressed in a variety of acute and chronic myeloid leukemia cells. Cytotoxic T lymphocytes specific for a PR3-derived peptide have been shown to specifically lyse leukemia cells that overexpress PR3. This review will focus on PR3 and the characteristics of PR3 that might implicate this particular antigen in the pathogenesis of WG and as target for immunotherapy in myeloid leukemias. We will discuss the genetic localization and gene regulation of PR3, the processing, storage, and expression of the PR3 protein, and the physiological functions of PR3, and compare this with the three other neutrophil-derived serine proteases: human leukocyte elastase, cathepsin G, and azurocidin. Three main differences are described between PR3 and the other serine proteases. This makes PR3 a very intriguing protein with a large array of physiological functions, some of which may play a role in ANCA-associated vasculitidis and myeloid leukemia.
Antibodies recognizing CD24 LAP epitope on human T cells enhance CD28 and IL-2 T cell proliferation
Authors: del C. Salamone María , Rosselot Carolina , Salamone Gabriela V , Barboza Marcos , Kado Miguel , Fainboim Leonardo 
Published: September 2022

AbstractMembrane expression of the CD24 molecule on activated T lymphocytes is not elucidated fully. We previously described the intracellular and cell-surface expression of the CD24 sialic acid-dependent epitope(s) on phytohemagglutinin-activated peripheral blood mononuclear cells. However, the CD24 core protein was not detected previously on human T cells. This study reinvestigated the expression and role of CD24 in T cell subsets. We analyzed binding of anti-CD24 monoclonal antibodies (mAbs) to sialic and leucine-alanine-proline (LAP) epitopes in resting and activated, normal T lymphocytes. CD24 LAP and CD24 sialic epitopes were detected on activated CD4- and CD8-positive cells. Although expression of CD24 sialic epitopes remained stably expressed in interleukin (IL)-2-dependent cultures, T cell expression of the LAP epitope was transient. Anti-LAP antibodies strongly enhanced the response of T cells to a combination of anti-CD3/CD28 mAbs and enhanced proliferative response induced by recombinant IL-2. We found similarities in the tissue distribution and function of the human CD24LAP molecule and the murine, heat-stable antigen, which suggests that CD24 might function as a signaling molecule on human T cells.
Characteristics of the free cytosolic calcium timelag following IgE-mediated stimulation of human basophils: significance for the nonreleasing basophil phenotype
Authors: MacGlashan Donald , Lavens-Phillips Sandra 
Published: September 2022

AbstractThese studies examine characteristics of the quiescent period (timelag) of the free cytosolic calcium ([Ca++]i) elevation that follows stimulation of human basophils through the IgE receptor. Previous studies established that the [Ca++]i timelag was sensitive to the rate of ligand binding, but little else is known about this response characteristic. The [Ca++]i timelag could be lengthened using antigenic stimulation that is rapid but only weakly induces secretion: tenfold differences in the “strength” of the stimulus, as assessed by histamine release, are associated with threefold differences in the timelag. Inhibiting p53/56lyn kinase with low concentrations of the specific inhibitor, PP1, lengthened the [Ca++]i timelag dramatically. PP1 was also found to delay the onset of syk phosphorylation and histamine release. Staurosporine and genistein, which are known to inhibit early tyrosine kinases, had, at best, only modest effects on the [Ca++]i timelag. Specific inhibitors of protein kinase C (PKC) had no effect on the [Ca++]i timelag, and direct activation of PKC with PMA had only very modest effects on the timelag. Contrary to expectations, basophils with the so-called nonreleasing phenotype demonstrated an IgE-mediated [Ca++]i response at the single-cell level. However, the length of [Ca++]i timelag in nonreleasing basophils was threefold longer than normally found in releasing basophils. Furthermore, the [Ca++]i response was significantly more asynchronous than in releasing basophils and lacking in a sustained [Ca++]ielevation. These studies indicate that the [Ca++]i timelag following stimulation through the IgE receptor is sensitive to inhibition of lyn kinase but not other agents that have been demonstrated to inhibit early tyrosine kinases previously. However, only one characteristic of the [Ca++]i response phenotype of nonreleasing basophils—the [Ca++]i timelag but not the absence of a sus-tained [Ca++]ielevation—could be mimicked by inhibition of lyn kinase with PP1.
Stromal derived factor-1α (SDF-1α) induces CD4+ T cell apoptosis via the functional up-regulation of the Fas (CD95)/Fas ligand (CD95L) pathway
Authors: Colamussi Maria Luisa , Secchiero Paola , Gonelli Arianna , Marchisio Marco , Zauli Giorgio , Capitani Silvano 
Published: September 2022

AbstractStromal-derived factor-1α (SDF-1α), the high-affinity ligand of CXC-chemokine receptor 4 (CXCR4), induced a progressive increase of apoptosis when added to the Jurkat CD4+/CXCR4+ T cell line. The SDF-1α-mediated Jurkat cell apoptosis was observed in serum-free or serum-containing cultures, peaked at SDF-1α concentrations of 10–100 ng/ml, required 3 days to take place, and was completely blocked by the z-VAD-fmk tripeptide caspase inhibitor. Although SDF-1α did not modify the expression of TNF-α or that of TNF-RI and TNF-RII, it increased the expression of surface Fas/APO-1 (CD95) and intracellular Fas ligand (CD95L) significantly. Moreover, the ability of SDF-1α to induce apoptosis was inhibited by an anti-CD95 Fab′ neutralizing antibody. These findings suggest a role for SDF-1α in the homeostatic control of CD4+ T-cell survival/apoptosis mediated by the CD95-CD95L pathway.
Cloning, mRNA distribution, and functional expression of an avian counterpart of the chemokine receptor/HIV coreceptor CXCR4
Authors: Liang Thomas S , Hartt Jennifer K , Lu Shuyan , Martins-Green Manuela , Gao Ji-Liang , Murphy Philip M 
Published: September 2022

AbstractThe chemokine signaling system, which coordinates the basal and emergency trafficking of leukocytes, presumably coevolved with the hematopoietic system. To study its phylogenetic origins, we used the open reading frame (ORF) of the human chemokine receptor CXCR4 as a genomic probe, since in mammals it is the most highly conserved chemokine receptor known. CXCR4 cross-hybridized to genomic DNA from mouse and chicken, but not zebrafish, Drosophila, orCaenorhabditis elegans. Accordingly, we cloned the corresponding chicken cDNA. The ORF is 359 codons long versus 352 for human CXCR4, and encodes a protein 82% identical to human CXCR4. In a calcium flux assay of receptor function, CHO-K1 cells stably transfected with the chicken cDNA responded specifically to human SDF-1, the specific ligand for CXCR4, but not to a panel of other chemokines tested at 100 nM. SDF-1 activated the cells in a dose-dependent manner (EC50 ∼5 nM), whereas parental CHO-K1 cells did not respond. The CHO-K1 cell transfectants also bound125I-SDF-1 specifically. Leukocytes from chicken peripheral blood expressed chCXCR4 mRNA and responded to human SDF-1 in a calcium flux assay with an EC50 similar to that for chCXCR4-transfected CHO cells, suggesting that this response is mediated by native chCXCR4. Analysis of chicken genomic DNA with the chicken cDNA as probe revealed a pattern consistent with a single copy gene, and the absence of any closely related genes. mRNA was detected in brain, bursa, liver, small and large intestine, embryonal fibroblasts, and blood leukocytes, but not in stomach or pancreas. These results, which identify the first functional non-viral, non-mammalian chemokine receptor, suggest that the origins of a functional chemokine system extend at least to birds and suggest that, as in mammals, CXCR4 functions in many avian tissues.
Retinoic acid up-regulates myeloid ICAM-3 expression and function in a cell-specific fashion—evidence for retinoid signaling pathways in the mast cell lineage
Authors: Babina Magda , Mammeri Kerstin , Henz Beate M 
Published: September 2022

AbstractInvestigation of mast cell responsiveness toward retinoic acid (RA) revealed selective promotion of ICAM-3 expression in the human mast cell line HMC-1. This process was dose- and time-dependent and detectable by flow cytometry, Western blot analysis, ELISA, and Northern blot analysis. ICAM-3 modulation was found to be cell-type dependent, detectable also for HL-60 cells and monocytes but not U-937 and only weakly for KU812 cells. Terminally differentiated skin mast cells also failed to up-modulate their ICAM-3, suggesting the requirement for some degree of immaturity for the process. RA-mediated effects on ICAM-1 expression, studied in parallel, were clearly distinct from those on ICAM-3. Investigation of retinoid receptor expression, known to mediate intracellular RA signaling, revealed presence of RARα, RARγ, RXRβ, and RXRγ transcripts in all cell lines studied, and HMC-1 cells were the only line lacking RXRα. RARβ, not expressed at baseline, was induced by RA in a fashion obviously correlating with ICAM-3 up-regulation. Increased ICAM-3 expression was of functional significance, such that processes stimulated or co-stimulated via ICAM-3 (homotypic aggregation, IL-8 secretion) were clearly enhanced upon RA pretreatment, suggesting that RA may contribute via hitherto unrecognized pathways to immune function and host defense.
Alternative versus classical macrophage activation during experimental African trypanosomosis
Authors: Namangala Boniface , De Baetselier Patrick , Noël Wim , Brys Lea , Beschin Alain 
Published: September 2022

AbstractThe type I/type II cytokine balance may influence the development of different subsets of suppressive macrophages, i.e., classically activated macrophages (caMφ, type I) versus alternatively activated macrophages (aaMφ, type II). Recently, we showed that although mice infected with phospholipase C-deficient (PLC−/−) Trypanosoma brucei brucei exhibit a clear shift from type I to the type II cytokine production, wild type (WT)-infected mice remain locked in a type I cytokine response. In the present study, phenotype and accessory cell function of macrophages elicited during WT and PLC−/−T. b. brucei infection were compared. Results indicate that caMφ develop in a type I cytokine environment in the early phase of WT and PLC−/− trypanosome infection, correlating with inhibition of T cell activation triggered by a mitogen, a superantigen, or an antigen. In the late stage of infection, only PLC−/−-infected mice resisting the infection develop type II cytokine-associated aaMφ correlating with impaired antigen- but not mitogen- or superantigen-induced T cell activation.
Inhibition of glucocorticoid-mediated, caspase-independent dendritic cell death by CD40 activation
Authors: Kim Kwang Dong , Choe Yong-Kyung , Choe In Seong , Lim Jong-Seok 
Published: September 2022

AbstractGlucocorticoids (GC) are potent anti-inflammatory and immunosuppressive agents that act on a variety of immune cells, including T cells, monocytes/macrophages, osteoclasts, and dendritic cells (DC). However, the mechanism(s) by which GC exert anti-inflammatory effects is still largely unknown. It is already well known that GC treatment inhibits DC maturation and interleukin (IL)-12 production by DC. In this study, we investigated the apoptosis induction of DC by a synthetic GC, dexamethasone (Dex). The stimulation with Dex resulted in DC apoptosis in a dose- and time-dependent manner as it was measured by determining annexin V-positive cells and mitochondrial potential. In contrast, monocytes that are precursor cells of DC are resistant to Dex-mediated apoptosis. The Dex-induced apoptosis of DC was independent of caspase activation because it was not inhibited by the broad caspase inhibitor, Z-VAD-fmk. It is interesting that agonistic CD40 antibody completely inhibited Dex-induced cell death, whereas other inflammatory stimuli did not show the same effect, suggesting that CD40 signaling may selectively modulate GC-mediated DC apoptosis. Taken together, our findings revealed an important role of GC and CD40 signaling in the regulation of immune responses in which DC play a key role in the inflammatory process of various immunomediated diseases.
Lymphocytes induce monocyte chemoattractant protein-1 production by renal cells after Fcγ receptor cross-linking: role of IL-1β
Authors: Rovin Brad H , Lu Ling , Marsh Clay B 
Published: September 2022

AbstractLeukocyte recruitment to the kidney in immune complex disease like systemic lupus erythematosus (SLE) is mediated in part by local expression of chemokines such as monocyte chemoattractant protein-1 (MCP-1). Recent studies from this laboratory demonstrated that cross-linking FcγR on lymphocytes causes release of a soluble factor that induces monocyte chemokine production. To explain the induction of renal chemokine expression in immune complex disease, we postulated that this lymphocyte factor stimulates renal parenchymal cell MCP-1 expression. To test this hypothesis, human peripheral blood lymphocytes were incubated on immobilized IgG, a model for immune complex FcγR cross-linking. Supernatants from these lymphocyte cultures significantly increased MCP-1 production by human mesangial, glomerular capillary endothelial, and proximal tubular epithelial cells. Mesangial cells incubated on immobilized IgG or with soluble, preformed immune complexes did not secrete MCP-1 above control levels. Lymphocyte supernatant-induced MCP-1 production appeared to be dependent on the presence of interleukin (IL)-1β in the supernatant. Removing IL-1β from the supernatants, antagonizing its activity, or preventing conversion to mature IL-1β abrogated renal cell MCP-1 expression by the lymphocyte supernatants. These data demonstrate that in response to cross-linking FcγR, lymphocytes induce renal cell MCP-1 expression by secreting IL-1β. Renal chemokine expression in immune complex disease may thus be triggered as lymphocytes traffic through the kidney and encounter deposited immune complexes.
Divergent effects of tumor necrosis factor α on apoptosis of human neutrophils
Authors: van den Berg J Merlijn , Weyer Sebastiaan , Weening Jan J , Roos Dirk , Kuijpers Taco W 
Published: September 2022

AbstractApoptosis of neutrophils is a key mechanism to control the intensity of the acute inflammatory response. Previously, the cytokine tumor necrosis factor α (TNF-α) was reported by some to have pro-apoptotic and by others to have anti-apoptotic effects on neutrophils. The aim of this study was to explain these contradictory results. We found that TNF-α at low concentrations strongly decreased apoptosis of neutrophils. However, at higher concentrations, TNF-α lost its protective effects, and also reversed the protective effects of interferon-γ (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF). This pro-apoptotic effect of TNF-α was blocked by anti-CD11b and was absent in neutrophils from patients with chronic granulomatous disease, which cannot produce toxic oxygen metabolites. Under these circumstances, we found that TNF-α retained its anti-apoptotic effects even at high concentrations. In conclusion, the protective effects against apoptosis of IFN-γ, GM-CSF, and TNF-α itself are overruled when the concentration of TNF-α is high enough to produce a respiratory burst. These dual, concentration-dependent effects of TNF-α provide an explanation for previous controversial reports and support a dominant role for TNF-α in neutrophil apoptosis.
Caspase-mediated cleavage of TRAF3 in FasL-stimulated Jurkat-T cells
Authors: Lee Zang Hee , Lee Shee Eun , Kwack KyuBum , Yeo Whanho , Lee Tae Ho , Bae Sun Sik , Suh Pann-Ghill , Kim Hong-Hee 
Published: September 2022

AbstractThe tumor necrosis factor receptor (TNFR)-associated factor (TRAF) proteins play a central role in the early steps of signal transduction by TNFR superfamily proteins, which induce various cellular responses, including apoptosis. Influences of TRAF proteins on the regulation of cell death and physical interactions between TRAFs and caspases have been reported. In this study, we demonstrate that TRAF3 is proteolyzed during cell death in a caspase-dependent manner. TRAF3 was found to be cleaved by incubation with caspase3 in vitro and by Fas- or CD3-triggering in Jurkat-T cells. The Fas- or CD3-induced cleavage of TRAF3 was blocked by caspase inhibitors and by introduction of alanine substitutions for D347 and D367 residues. Furthermore, the amino-terminal fragment of TRAF3 showed a different intracellular localization from the full-length TRAF3 with preferential distribution to particulate fractions and the nucleus. These findings suggest that TRAF3 may be regulated by caspases during apoptosis of T cells.