bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic induction of MCP-1 and -2 by IL-1β and interferons in fibroblasts and epithelial cells
Authors: Struyf Sofie , van Coillie Els , Paemen Liesbet , Put Willy , Lenaerts Jean-Pierre , Proost Paul , Opdenakker Ghislain , van Damme Jo 
Published: January 2018

Abstract
Monocyte chemotactic protein (MCP)-1 and MCP-2, two closely related CC chemokines, are important mediators of monocyte and lymphocyte migration. These chemokines are secreted by various normal cell types, including fibroblasts, epithelial cells, and leukocytes, as well as by tumor cells. After stimulation with different cytokines and cytokine inducers the MCP-2 production levels are always lower than those of MCP-1. In human diploid fibroblasts cytokines differentially regulate chemokine induction, interleukin (IL)-1β and interferon (IFN)-γ being potent stimuli of MCP-1 and MCP-2, respectively. Co-stimulation of fibroblasts by 10 U/mL IL-1β and 20 ng/mL IFN-γ resulted in a synergistic induction of MCP-2, whereas the combined effect on MCP-1 and IL-6 production was rather additive. These findings were confirmed at the mRNA level by Northern blot analysis. In contrast, in human MG-63 fibroblastoid cells and HEp-2 epithelial cells, selected for their poor responsiveness to IL-1β and IFN-γ, MCP-2 as well as MCP-1 and IL-6 were synergistically induced, yielding protein levels that were increased 3- to 30-fold above the additive levels. When IFN-β was used as a co-stimulant of IL-1β, a similar synergistic induction of MCP-1 and MCP-2 was measured both at the protein and the mRNA level. It can be concluded that, when synergy occurred, the MCP-1 and MCP-2 expression levels reached a comparable maximum, indicative for an equal contribution of these chemokines in normal and pathological conditions.
Transcription factors that regulate monocyte/macrophage differentiation
Authors: Valledor Annabel F , Borràs Francesc E , Cullell-Young Martin , Celada Antonio 
Published: January 2018

Abstract
Although all the cells in an organism contain the same genetic information, differences in the cell phenotype arise from the expression of lineage-specific genes. During myelopoiesis, external differentiating signals regulate the expression of a set of transcription factors. The combined action of these transcription factors subsequently determines the expression of myeloid-specific genes and the generation of monocytes and macrophages. In particular, the transcription factor PU.1 has a critical role in this process. We review the contribution of several transcription factors to the control of macrophage development.
The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells
Authors: Mackey Matthew F , Barth Richard J , Noelle Randolph J 
Published: January 2018

Abstract
This review focuses on the emerging body of literature suggesting a critical role for CD40/CD154 interactions in antigen-presenting cell (APC) activation, CD4+ and CD8+ T cell priming, and effector T cell maturation. In this context effective antigen presentation involves not only T cell expansion and long-term survival but also the ability of the APC to guide the T cell response toward the Th1 (interferon-γ producing) or the Th2 (interleukin-4 producing) phenotype. We suggest a model to explain why CD40/CD154 interactions are critical for some helper and cytotoxic T cell responses, whereas others occur independently of this receptor/ligand pair. In addition, we will discuss the potential role for CD40/CD154 interactions in effector T cell maturation and cytokine production.
Endotoxemia, pentose cycle, and the oxidant/antioxidant balance in the hepatic sinusoid
Authors: Spolarics Zoltán 
Published: January 2018

Abstract
During the innate immune response, excessive release of reactive oxygen species (ROS) from sequestered phagocytes and activated resident macrophages represents the predominant component of oxidative stress in the liver and other tissues. The consequence of oxidative stress is determined by the status and adaptive changes of antioxidant pathways. In this review, we present evidence that the synchronized response of hepatic sinusoidal endothelial cells, the primary sites of phagocyte attachment, plays an important role in defense against phagocyte-derived ROS. An essential component of the metabolic adaptation of hepatic sinusoidal cells to lipopolysaccharide (LPS)-induced oxidative stress is the stimulated expression of glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of the pentose cycle (hexose monophosphate shunt, HMS). All major ROS-metabolic enzymes, i.e., glutathione peroxidase, glutathione reductase, catalase, superoxide dismutases, NADPH oxidase, and nitric oxide synthase, directly or indirectly depend on NADPH, which is produced in the HMS in these cells. The functional significance of up-regulated HMS within a particular cell type depends on the accompanying adaptive changes in ROS-metabolizing enzymes. In LPS-activated Kupffer cells, the elevated expression of glucose transporter GLUT1 and G6PD mainly serves primed production of superoxide anion, hydrogen peroxide, and nitric oxide. In sinusoidal endothelial cells, the LPS-induced response pattern of glucose- and ROS-metabolizing enzymes results in elevated ROS detoxifying capacity. The described studies also suggest the existence of an intercellular oxidant balance between prooxidant Kupffer cells and antioxidant endothelial cells in the hepatic micro-environment. Maintenance of the intercellular oxidant/antioxidant balance between phagocytes and endothelial cells may represent an important mechanism protecting the hepatic parenchyma against exogenous oxidative stress during the inflammatory response.
Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide modulate endotoxin-induced IL-6 production by murine peritoneal macrophages
Authors: Martínez Carmen , Delgado Mario , Pozo David , Leceta Javier , Calvo Juan R , Ganea Doina , Gomariz Rosa P 
Published: January 2018

Abstract
Vasoactive intestinal peptide (VIP) is a neuropeptide synthesized by immune cells that can modulate several immune aspects, including the function of cells involved in the inflammatory response, such as macrophages and monocytes. Production and release of cytokines by activated mononuclear phagocytes is an important event in the pathogenesis of ischemia-reperfusion injury. VIP has been shown to attenuate the deleterious consequences of this pathologic phenomenon. We have investigated the effects of VIP and PACAP38 on the production of interleukin-6 (IL-6), a proinflammatory cytokine, by endotoxin-activated murine macrophages. Both neuropeptides exhibit a dual effect on the IL-6 production by peritoneal macrophages. Whereas VIP and PACAP inhibit with similar dose-response curves the release of IL-6 from macrophages stimulated with a LPS dose range from 100 pg/mL to 10 μg/mL, both neuropeptides enhance IL-6 secretion in unstimulated macrophages and in macrophages stimulated with very low LPS concentrations (1-10 pg/mL). The inhibition on LPS-induced IL-6 production is specific, presumably mediated through a subtype of the PACAP-R. VIP and PACAP regulate the production of IL-6 at a transcriptional level. These results were correlated with an inhibition on both IL-6 expression and release in endotoxemic mice in vivo. These findings support the idea that in the absence of stimulation or in the presence of low doses of LPS, VIP and PACAP could play a role in immune system homeostasis. However, under toxicity conditions associated with high LPS doses, VIP and PACAP could act as protective mediators that regulate the excessive release of IL-6 in order to reduce inflammation or shock.
Physiological activation of human neutrophils down-regulates CD53 cell surface antigen
Authors: Mollinedo Faustino , Martín-Martín Belén , Gajate Consuelo , Lazo Pedro A 
Published: January 2018

Abstract
Tetraspanin transmembrane proteins have a metastasis suppressor effect by acting as cell motility brakes in tumor cells. CD53 is a panleukocyte antigen that belongs to the tetra-span superfamily. Human neutrophils express high levels of CD53. We tested the hypothesis that this antigen level changes when cells are activated. Treatment of human neutrophils with their physiological activators, tumor necrosis factor α or platelet-activating factor, resulted in down-regulation of this antigen from the cell surface, as assessed by immunofluorescence flow cytometry. Similar responses were observed when neutrophils were stimulated with chemotactic N-formyl-methionyl-leucyl-phenylalanine, phorbol ester, or the calcium ionophore ionomycin. The CD53 antigen down-regulation upon neutrophil stimulation was further confirmed by immunoblotting analysis and was not correlated with a change in the level of CD53 transcripts. This CD53 antigen down-regulation paralleled that of CD43 and CD44 antigens in these cells, despite their different protein structure. The down-regulation of the three antigens CD53, CD43, and CD44 could be inhibited by phenylmethylsulfonyl fluoride, suggesting that CD53 antigen down-regulation is the result of the activation of a proteolytic mechanism. Down-regulation of CD53 antigen level, as a result of cellular stimulation, might play a role in the different aspects of neutrophil biology, by modulating its interactions on the cell surface.
Blocking cytokines with genes
Authors: Evans C H , Ghivizzani S C , Robbins P D 
Published: January 2018

Abstract
The pathophysiology of rheumatoid arthritis (RA) is primarily driven by proinflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor α. Several biological agents have been identified that effectively block the activity of these cellular messengers, and administration of these agents to animal models of RA and human patients has been found to have therapeutic benefit. The application of gene therapy for the treatment of RA and other articular diseases is being explored to overcome current limitations with delivery of therapeutics to joint tissues. To date, laboratory research has focused on two main areas: (1) evaluation of gene delivery approaches and (2) identification of therapeutic gene products. Considerable progress has been reported with the use of local gene delivery to synovial cells by both in vivo and ex vivo methods and by systemic administration of gene delivery vectors via the circulation. Gene products that have therapeutic efficacy in animal models of RA include: IL-1 receptor antagonist, soluble IL-1 receptor I, soluble tumor necrosis factor receptor II, viral IL-10, and transforming growth factor β, among others. The success of these laboratory studies has led to the implementation of a Phase I clinical trial to asses the safety and feasibility of using gene therapy in the treatment of RA. J. Leukoc. Biol. 64: 55–61; 1998.
Molecular mimicry of the inflammation modulatory proteins (IMPs) of poxviruses: evasion of the inflammatory response to preserve viral habitat
Authors: Howard Jeremy , Justus David E , Totmenin Alexei V , Shchelkunov Sergei , Kotwal Girish J 
Published: January 2018

Abstract
Microorganisms encode numerous immunomodulators that resemble, in structure and function, molecules captured over the millennia from their hosts [G. J. Kotwal J. Leukoc. Biol. 62, 415–429]. The vaccinia virus complement control protein (VCP) was the first soluble microbial protein to have a postulated role in the immunomodulation and evasion of host defense [G. J. Kotwal and B. Moss Nature 355, 176–179]. Purified bioactive VCP has been shown to bind to C3 and C4, block the complement cascade at multiple sites [G. J. Kotwal et al. Science 250, 827–830; R. Mckenzie, G. J. Kotwal et al. J. Infect. Dis. 166, 1245–1250] and exhibit a greater potency than the human complement 4b binding protein, C4b-BP [G. J. Kotwal, Am. Biotech. Lab. 9,76]. The importance of this protein to poxviruses was further demonstrated in rabbits and guinea pigs through the use of recombinant virus lacking an intact DNA coding for VCP [Isaacs, G. J. Kotwal, and B. Moss Proc. Natl. Acad. Sci. 89, 628–672]. Studies in mice have shown that the homolog of VCP in cowpox virus (CPV), referred to as the inflammation modulatory protein (IMP) can, in a mouse model, significantly diminish the specific footpad swelling response [C. G. Miller, S. N. Shchelkunov, and G. J. Kotwal Virol. 229, 126–133]. To determine the precise cellular changes at the site of infection, BALB/c mice were subcutaneously injected (in the backs) with CPV or a recombinant virus lacking IMP, CPV-IMP. Differences in histology were observed by staining the adjoining skin tissue sections with hematoxylin & eosin or by removal of the connective tissue and staining with May-Grunwald-Geimsa. All mice that were injected with the CPV-IMP experienced severe tissue destruction and formation of nodular lesions compared with the mice injected with CPV. Microscopic examination indicated significantly greater cellular infiltration and destruction of skeletal muscle cells in the sections of connective tissue and adjoining skin tissue, respectively, of the mice injected with the CPV-IMP [G. J. Kotwal et al. Mol. Cell. Biochem. in press]. Thus IMP preserves the tissue at the site of infection (viral habitat). In this review, we present evidence for molecular mimicry and evolutionary relationship to other homologs of IMP and discuss their relationships with other IMPs such as the poxviral chemokine and cytokine receptor-like proteins. J. Leukoc. Biol. 64: 68–71; 1998.
Antinociceptive effect of the calcium-binding protein MRP-14 and the role played by neutrophils on the control of inflammatory pain
Authors: Giorgi R , Pagano R L , Dias M A Amorim , Aguiar-Passeti T , Sorg C , Mariano M 
Published: January 2018

Abstract
Macrophages secrete a variety of chemical mediators that play a central role in the pathophysiology of inflammatory pain. Therefore, the activation or deactivation of these cells in an inflammatory focus could modulate the intensity of the algogenic response. Based on these premises and on our previous demonstration that the calcium-binding protein MRP-14, highly expressed in neutrophils, deactivates activated macrophages in vitro, we decided to investigate the role of MRP-14 and of neutrophils in the control of inflammatory pain in mice. Our results show that this protein is endowed with antinociceptive activity. When tested in the writhing model it was able to inhibit pain response but did not change the behavior of the animals in the hot plate test. This observation indicates that MRP-14 down-regulates inflammatory but not central pain. Using a model of acute neutrophilic peritonitis induced by glycogen, a close correlation between neutrophil migration and antinociception was detected. Surgical adrenalectomy demonstrated that the antinociceptive response induced by glycogen was not due to endogenous liberation of glucocorticoids. The treatment of animals either with a monoclonal antibody anti-MRP-14 or a monoclonal antibody that depletes the animals of neutrophils reverts the antinociceptive response observed in the glycogen-induced peritonitis. These data define the calcium-binding protein MRP-14 as a novel mediator for the control of inflammatory pain and consequently discloses an anti-inflammatory role for the neutrophil. J. Leukoc. Biol. 64: 214–220; 1998.
Expression of mRNA encoding neurotrophins and neurotrophin receptors in human granulocytes and bone marrow cells—enhanced neurotrophin-4 expression induced by LTB4
Authors: Laurenzi Maria Assunta , Beccari Tommaso , Stenke Leif , Sjölinder Mikael , Stinchi Sofia , Lindgren Jan Åke 
Published: January 2018

Abstract
The expression of neurotrophin and neurotrophin receptor mRNAs in human granulocytes and bone marrow cells was examined using ribonuclease protection assay and reverse transcription-polymerase chain reaction. The granulocytes expressed mRNA coding for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-4 (NT-4), but not neurotrophin-3 (NT-3). Moreover, the inflammatory mediator leukotriene B4 (LTB4) up-regulated the expression of NT-4 mRNA in granulocytes, but did not affect the expression of other neurotrophin mRNAs. Granulocytes generally lacked expression of mRNA coding for neurotrophin receptors. In contrast, human bone marrow cells consistently expressed mRNA for trkB (the BDNF and NT-4 receptor) and displayed variable expression of mRNA coding for trkA (the tyrosine kinase NGF receptor) and LNGFR (the low-affinity NGF receptor), whereas mRNA for trkC (the NT-3 receptor) was not expressed. Contrary to granulocytes, normal bone marrow cells generally expressed only low levels of mRNA encoding BDNF and NT-4. Expression of mRNA encoding NGF and NT-3 was not detected. However, significantly increased expression of BDNF mRNA was observed when bone marrow cells from patients with chronic myeloproliferative disorders (MPD) were analyzed. The results suggest that neurotrophins may act as granulocyte-derived effector molecules and that human bone marrow cells may be targets for these compounds, in particular BDNF and NT-4. J. Leukoc. Biol. 64: 228–234; 1998.
Characterization of cytokine differential induction of STAT complexes in primary human T and NK cells
Authors: Yu Cheng-Rong , Young Howard A , Ortaldo John R 
Published: January 2018

Abstract
Cytokines, IL-2, IL-4, IL-6, IL-7, IL-12, and IL-15 are key regulators of human peripheral blood T and NK cell activation and differentiation but the precise mechanisms that give rise to their differential activities within these cells are not clear. Recent studies reveal that a family of transcription factors, signal transducers and activators of transcription (STATs) directly mediate many cytokine signals. We analyzed the activation of STATs in primary human T and NK cells by a variety of specific cytokines. We demonstrate that IL-12 induces STAT4 only in freshly isolated primary NK cells, but not in primary T cells, consistent with the lack of the IL-12 receptor in resting T cells. In contrast, IL-4 induces different Cε GAS DNA-protein binding complexes in both T and NK cells. Moreover, IL-4 costimulation with IL-2 or IL-12 does not alter their own preferential GAS-like DNA binding patterns when Cε-, FcγRI-, and SIE GAS motif containing oligonucleotide probes are compared, suggesting that induction of GAS-like DNA-protein binding complexes by IL-2, IL-4, and IL-12 is highly selective and represents one important factor in determining specific gene activation. In addition, IL-6 and IL-2 synergistically induce homo- and heterodimerized STAT1α and STAT3 in both NK and T cells, consistent with their reported synergism in modulating perforin gene expression. We further demonstrated that IL-2, -7, and -15 induce multiple STAT proteins, including STAT5a, STAT5b, STAT1α, STAT3, and another unidentified FcγRI GAS DNA-binding protein. Finally, we observed that activated STAT5a and STAT5b proteins form distinct FcyRI GAS binding patterns in T and NK cells, suggesting that they might have different roles in gene regulation. Our data provide evidence that the differential responses in gene expression and cell activation seen in primary NK and T cells on direct stimulation with different cytokines may be a direct result of distinct activation of STAT transcription factors. J. Leukoc. Biol. 64: 245–258; 1998.
Modulation of P2X7 nucleotide receptor expression by pro- and anti-inflammatory stimuli in THP-1 monocytes
Authors: Humphreys Benjamin D , Dubyak George R 
Published: January 2018

Abstract
Regulation of P2X7 receptor expression is of interest because activation of this receptor by extracellular ATP triggers maturation and release of the proinflammatory cytokine interleukin-1β (IL-1β) in monocytes and macrophages. We report that interferon-γ (IFN-γ) and tumor necrosis factor α (TNF-α) synergistically induce P2X7R mRNA and functional responses in the human THP-1 monocytic cell line. Induction was dose dependent, with maximal functional activity requiring 1000 units/mL IFN-γ and 10 ng/mL TNF-α and incubations of 36–72 h. The up-regulation of P2X7R function by lipopolysaccharide (LPS)/IFN-γ and TNF-α/IFN-γ was markedly attenuated by coincubation with prostaglandin E2 or the cell permeant cyclic AMP analog dibutyryl cAMP (Bt2cAMP). Bt2cAMP did not significantly alter P2X7 function in HEK-293 cells stably transfected with the human P2X7 cDNA, indicating that Bt2cAMP does not exert a generalized effect on P2X7R synthesis or downstream signal transduction. These studies demonstrate that elevated cAMP negatively modulates P2X7R expression. J. Leukoc. Biol. 64: 265–273; 1998.
Tumor-induced immune dysfunction: the macrophage connection
Authors: Elgert Klaus D , Alleva David G , Mullins David W 
Published: January 2018

Abstract
Although macrophages (Mφs) mediate tumor cytotoxicity, display tumor-associated antigens, and stimulate antitumor lymphocytes, cancer cells routinely circumvent these host-mediated immune activities, rendering the host incapable of mounting a successful antitumor immune response. Evidence supporting a direct causal relationship between cancer and immune dysfunction suggests that the presence of neoplastic tissue leads to immunologic degeneration. Furthermore, substantial data demonstrate that tumor growth adversely alters Mφ function and phenotype. Thus, although Mφs can serve as both positive and negative mediators of the immune system, the importance of Mφs in tumor-induced immune suppression remains controversial. This review focuses on the evidence that tumor-derived molecules redirect Mφ activities to promote tumor development. Tumors produce cytokines, growth factors, chemotactic molecules, and proteases that influence Mφ functions. Many tumor-derived molecules, such as IL-4, IL-6, IL-10, MDF, TGF-β1, PGE2, and M-CSF, deactivate or suppress the cytotoxic activity of activated Mφs. Evidence that tumor-derived molecules modulate Mφ cytotoxicity and induce Mφ suppressor activity is presented. This information further suggests that Mφs in different in vivo compartments may be differentially regulated by tumor-derived molecules, which may deactivate tumor-proximal (in situ) Mφ populations while concurrently activating tumordistal Mφs, imparting a twofold insult to the host’s antitumor immune response. J. Leukoc. Biol. 64: 275–290; 1998.
Spontaneous and Fas-mediated apoptosis are diminished in umbilical cord blood neutrophils compared with adult neutrophils
Authors: Allgaier Bernhard , Shi Min , Luo DeFang , Koenig Joyce M 
Published: January 2018

Abstract
Apoptosis mediates neutrophil (PMN) phagocytosis and is influenced by cytokines and the Fas/Fas ligand pathway. To determine whether apoptosis of cord blood PMN differs from those of adults, cultured PMN were evaluated by morphological analysis, flow cytometry (TUNEL assay), and DNA gel electrophoresis. In addition, we studied the effect of anti-Fas IgM or cycloheximide on induction of PMN apoptosis. Spontaneous apoptosis (24 h) was less in cord blood PMN (mean ± SD; 29 ± 9 vs. adults, 56 ± 14%, P &lt; 0.001). Treatment (6 h) with anti-Fas IgM induced less apoptosis in cord blood PMN (24 ± 6 vs. adults, 63 ± 7%, P &lt; 0.001), as did treatment with cycloheximide (13 ± 10 vs. adults, 55 ± 16%, P &lt; 0.01). These data suggest the pre-existence of proteins that inhibit apoptosis or the absence of those that promote apoptosis in cord blood PMN. J. Leukoc. Biol. 64: 331–336; 1998.