bluuebunny/crossref_metadata_2025_split huggingface dataset:
Laminin binding to the calreticulin fragment vasostatin regulates endothelial cell function
Authors: Yao Lei , Pike Sandra E , Tosato Giovanna 
Published: September 2022

AbstractVasostatin, the 1–180 amino acids NH2 domain of calreticulin, inhibits endothelial cell proliferation, angiogenesis, and tumor growth, but the mechanisms underlying these effects areunclear. We show that endothelial cells express the extracellularmatrix protein laminin, including chains α5 and γ1 and thatvasostatin specifically binds to laminin. When added to endothelialcell cultures, vasostatin specifically inhibits endothelial cellattachment to laminin and by this mechanism, can reduce subsequentendothelial cell growth induced by basic fibroblast growth factor. Asan angiogenesis inhibitor that specifically disrupts endothelial cellattachment to components of the extracellular matrix, vasostatin has aunique potential as a cancer therapeutic.
Molecular mechanisms of glucocorticoid antiproliferative effects: antagonism of transcription factor activity by glucocorticoid receptor
Authors: Almawi Wassim Y , Melemedjian Ohannes K 
Published: September 2022

AbstractGlucocorticoids (GCs) exert their anti-inflammatory andimmunosuppressive effects by inhibiting the expression of cytokines andadhesion molecules. The molecular basis of GC action lies in theircapacity to diffuse through the cell membrane and bind their cytosolicGC receptor (GR), which subsequently undergoes nuclear translocationand modulates transcriptional activation through association withpromoter elements, GC response elements (GRE). GR also antagonized theactivity of transcription factors, including NF-κB, NF-AT, and AP-1,through direct and indirect mechanisms. GCs induced the genetranscription and protein synthesis of the NF-κB inhibitor, IκB. Activated GR antagonized transcription factor activity throughprotein:protein interaction. This involved complexing with andinhibition of transcription factor binding to DNA (simple model),association with factor bound at its DNA site (compositemodel), and/or through interaction of GRE-bound GR withDNA-bound transcription factor (transmodulation model). Finally, GRcompeted with transcription factors for nuclear coactivators(competition model), including CBP and p300. Remarkably, GR did notaffect the assembly of the preinitiation complex but acted proximallyin inhibiting transcription factor activity and thus transcriptionalinitiation.
Macrophages from IL-12p40-deficient mice have a bias toward the M2 activation profile
Authors: Bastos Karina R B , Alvarez José M , Marinho Cláudio R F , Rizzo Luiz V , D'Império Lima Maria Regina 
Published: September 2022

AbstractRecent studies have provided evidence that macrophages from Th1-prone mouse strains respond with an M1 profile, and macrophages from Th2-prone mouse strains respond with an M2 profile, characterized by the dominant production of NO or TGF-β1, respectively. We have shown that peritoneal macrophages from IL-12p40 gene knockout mice have a bias toward the M2 profile, spontaneously secreting large amounts of TGF-β1 and responding to rIFN-γ with weak NO production. Moreover, IL-12p40KO macrophages are more permissive to Trypanosoma cruzi replication than their wild-type littermate cells. Prolonged incubation with rIL-12 fails to reverse the M2 polarization of IL-12p40KO macrophages. However, TGF-β1 is directly implicated in sustaining the M2 profile because its inhibition increases NO release from IL-12p40KO macrophages. IFN-γ deficiency is apparently not the reason for TGF-β1 up-regulation, because rIFN-γKO macrophages produce normal amounts of this cytokine. These findings raise the possibility that IL-12 has a central role in driving macrophage polarization, regulating their intrinsic ability to respond against intracellular parasites.
Glutathione redox regulates lipopolysaccharide-induced IL-12 production through p38 mitogen-activated protein kinase activation in human monocytes: role of glutathione redox in IFN-γ priming of IL-12 production
Authors: Utsugi Mitsuyoshi , Dobashi Kunio , Koga Yasuhiko , Shimizu Yasuo , Ishizuka Tamotsu , Iizuka Kunihiko , Hamuro Junji , Nakazawa Tsugio , Mori Masatomo 
Published: September 2022

AbstractWe examined whether changes in intracellular reduced (GSH) or oxidized (GSSG) glutathione of human monocytes regulate lipopolysaccharide (LPS)-induced IL-12 production and defined the molecular mechanism that underlies glutathione redox regulation. Monocytes exposed to glutathione reduced form ethyl ester (GSH-OEt) or maleic acid diethyl ester (DEM) increased or decreased the intracellular GSH/GSSG ratio, respectively. LPS-induced IL-12 production and p38 mitogen-activated protein (MAP) kinase activation were enhanced by GSH-OEt but suppressed by DEM. Selective p38 inhibitors showed that p38 promoted GSH-OEt-enhanced IL-12 production. Furthermore, IFN-γ priming increased the GSH/GSSG ratio and enhanced IL-12 production through p38, and DEM negated the priming effect of IFN-γ on p38 activation and IL-12 production as well as on the GSH/GSSG ratio. These findings reveal that glutathione redox regulates LPS-induced IL-12 production from monocytes through p38 MAP kinase activation and that the priming effect of IFN-γ on IL-12 production is partly a result of the glutathione redox balance.
Occupancy of adenosine A2a receptors promotes fMLP-induced cyclic AMP accumulation in human neutrophils: impact on phospholipase D activity and recruitment of small GTPases to membranes
Authors: Thibault Nathalie , Burelout Chantal , Harbour Danielle , Borgeat Pierre , Naccache Paul H , Bourgoin Sylvain G 
Published: September 2022

AbstractThe aim of this study was to assess in human neutrophils theimplication of an adenosine 3′,5′-cyclic monophosphate (cAMP)-dependentpathway in the inhibitory effects of A2a receptor engagement. We foundthat Ro20-1724, a cAMP phosphodiesterase inhibitor, in the presence ofadenosine deaminase (ADA) or A2a receptor antagonists renderedtransient the fMLP-induced sustained increases in cAMP levels. The roleof A2a receptor stimulation was demonstrated by the ability of the A2areceptor agonist, CGS21680, to prevent ADA-mediated reduction of thepersistent cAMP elevation induced by fMLP. Persistent cAMP elevationcorrelated with inhibition of fMLP-induced PLD activation andrecruitment of Arf, RhoA, and PKC to membranes. The suppressive effectof CGS21680 or isoproterenol, a β-adrenergic receptor agonist, wasincreased by Ro20-1724 or by the adenylyl cyclase activator, forskolin, and reversed, at least in part, by the inhibitor of adenylyl cyclase,2′,5′-dideoxyadenosine. The activator of protein kinase A (PKA),Sp-cAMP inhibited fMLP-induced PLD activation and translocation of Arfand RhoA to membranes. In contrast, the suppression by A2a receptorstimulation of fMLP-induced PLD activation and cofactor recruitment wasantagonized by PKA inhibitors, Rp-cAMP and H89. In conclusion, A2areceptor occupancy by extracellular adenosine inhibits fMLP-inducedneutrophil activation via cAMP and PKA-regulated events.
Distinct fates of monocytes and T cells directly activated byPseudomonas aeruginosaexoenzyme S
Authors: Epelman Slava , Neely Graham G , Ma Ling Ling , Gjomarkaj Mark , Pace Elisabetta , Melis Mario , Woods Donald E , Mody Christopher H 
Published: September 2022

AbstractGram-negative infections can cause overwhelming inflammatory responses. Although factors other than LPS are clearly involved, these factors and their mechanisms of action have been poorly defined. During studies of LPS-independent inflammatory responses of the gram-negative pathogen Pseudomonas aeruginosa, an important virulence factor (exoenzyme S) was shown to be a potent mitogen for T cells. The current work demonstrates that exoenzyme S selectively induced transcription and secretion of biologically active cytokines and chemokines (chemotactic for neutrophils and T cells) from monocytes. Exoenzyme S stimulated highly purified monocytes independent of T cells. In addition, exoenzyme S stimulated T cells directly; neither T-cell activation (CD69) nor apoptosis (hypodiploidy) required the presence of monocytes. However, T-cell activation was enhanced via a noncontact-dependent mechanism as a result of the secretion of TNF-α and IL-6. This study identifies a unique property of a gram-negative-derived microbial product capable of activating multiple cell types and suggests a mechanism by which exoenzyme S contributes to the immunopathogenesis of cystic fibrosis and sepsis in patients infected with P. aeruginosa.
IFN-α2a induces IP-10/CXCL10 and MIG/CXCL9 production in monocyte-derived dendritic cells and enhances their capacity to attract and stimulate CD8+ effector T cells
Authors: Padovan Elisabetta , Spagnoli Giulio C , Ferrantini Maria , Heberer Michael 
Published: September 2022

AbstractType I IFNs are immunomodulatory factors that possibly influence the properties of tissue-resident dendritic cells. Here, we have investigated the capacity of IFN-α2a to enhance DC chemoattractive and stimulatory capacity toward CD8+ T lymphocytes. Phenotypically, IFN-α2a-treated DC (IFN-DC) showed an increased expression of costimulatory and antigen-presenting molecules, maintained even after withdrawal of the cytokine. IFN-α2a enhanced DC stimulatory capacity toward CD8+ T cells, as assessed by increased MLR responses and induction of MART-126–35-specific CTLs in vitro. No functional CCR7 chemokine receptor could be induced. Instead, high amounts of IP-10/CXCL10 and MIG/CXCL9 chemokines were produced. Freshly isolated CD8+RO+ cells and PHA-activated CD8+ T cells migrated efficiently in response to IFN-DC-conditioned medium, and the migration could be inhibited by neutralizing the CXCR3 receptor on responder cells. These results suggest that type I IFNs could enhance the elicitation of class I-restricted effector functions in vivo in the periphery by modulating DC chemoattractive properties.
Oxidized low-density and high-density lipoproteins regulate the production of matrix metalloproteinase-1 and -9 by activated monocytes
Authors: Ardans Jeanette A , Economou Antaeus P , Martinson James M , Zhou Min , Wahl Larry M 
Published: September 2022

AbstractMonocytes/macrophages are prominent in atherosclerotic plaques where the vascular remodeling and plaque rupture may be influenced by the lipids and cytokines at these sites. Therefore, we evaluated the effects of factors found within the vascular wall, such as cytokines, oxidized low-density lipoprotein (ox-LDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), on monocyte-derived matrix metalloproteinase-1 (MMP-1) and -9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1). ox-LDL, LDL, and HDL alone had no effect on MMP-1, MMP-9, or TIMP-1 production. However, in the presence of tumor necrosis factor (TNF)-α and GM-CSF, ox-LDL enhanced MMP-1 significantly by two- to threefold, increased MMP-9 slightly, and had no effect on TIMP-1 production. In contrast, HDL suppressed the induction of MMP-1 by TNF-α and GM-CSF as well as the ox-LDL-mediated increase in MMP-1 production. The enhancement of MMP-1 production by ox-LDL occurred through, in part, a prostaglandin E2 (PGE2)-dependent pathway as indomethacin suppressed and PGE2 restored MMP-1 production. This conclusion was supported further by ox-LDL-mediated increases in PGE2 and cyclooxygenase-2 (COX-2) production. These data suggest that the interaction of primary monocytes with ox-LDL and proinflammatory cytokines may contribute to vascular remodeling and plaque rupture.
Rapid static adhesion of human naïve neutrophil to naïve xenoendothelium under physiologic flow is independent of Galα1,3-gal structures
Authors: Sheikh Sajila , Parhar Ranjit , Al-Mohanna Futwan 
Published: September 2022

AbstractAdhesion interactions under flow have long been known to depend on applied wall shear stress. We investigated the ability of human naïve neutrophils to adhere to xenogeneic endothelial cells under static and flow conditions. We demonstrate that human naïve neutrophils bind to xenogeneic endothelial cells under flow conditions. This binding is dependent on the applied stress and is independent of Galα1,3-gal structures, ICAM-1, or its counter ligands LFA-1α and Mac-1. The binding was rapid and is characterized by stationary attachment with no obvious rolling or change in morphology. This binding leads to a transient increase in intracellular-free calcium levels in xenogeneic but not allogeneic-endothelial cells with occasional oscillations that persist long after the initial contact between the two cell types. Previous activation of xenoendothelium by autologous serum or human TNF-α augments binding of human naïve neutrophils to the endothelial cells. Our data suggest novel interaction sites between the xenogeneic endothelial cells and human naïve neutrophils.
Pulmonary eosinophilia in mice devoid of interleukin-5
Authors: Domachowske Joseph B , Bonville Cynthia A , Easton Andrew J , Rosenberg Helene F 
Published: September 2022

AbstractThe biology of the eosinophilic leukocyte—development, recruitment, and prolonged existence in somatic tissues—has been linked almost invariably to the actions of the “eosinophil” cytokine, interleukin-5 (IL-5). Here we demonstrate that pulmonary eosinophilia can occur in the absence of IL-5, as morphologically normal eosinophils are recruited to the lungs of virus-infected IL-5 −/− mice with kinetics and sequelae that are indistinguishable from those of their IL-5 +/+ counterparts. We conclude that pulmonary eosinophilia observed in response to primary paramyxovirus infection occurs via mechanisms that are distinct from those involved in eosinophil responses to allergens and in asthma. Furthermore, the presence of functional eosinophils in IL-5 −/− mice suggests the possibility of developmentally distinct subsets of what has been presumed to be a homogeneous leukocyte population.
Differential morphine tolerance development in the modulation of macrophage cytokine production in mice
Authors: Limiroli Elena , Gaspani Leda , Panerai Alberto E , Sacerdote Paola 
Published: September 2022

AbstractMorphine has been shown to affect cell-mediated and humoral immune parameters. In this study, we investigated the capacity of in vivo acute and chronic morphine treatment to modulate interleukin (IL)-10 and IL-12 production by LPS and interferon-γ-stimulated resident and thioglycollate-elicited murine peritoneal macrophages and the development of tolerance to these effects. One hour after the acute administration of 5, 10, and 20 mg/Kg morphine, a dose-related decrease of IL-10 and IL-12 levels was present. The pretreatment with naltrexone at doses up to 20 mg/Kg did not prevent the decrease of IL-10 and IL-12 induced by morphine. When the drug was administered chronically, a differential development of tolerance to the immune effects was observed. After 3 days of treatment, the effect of the acute challenge with 20 mg/Kg morphine on IL-12 was lost. In contrast, morphine-induced inhibition of IL-10 disappeared between 10 and 12 days of treatment, in parallel with tolerance to the antinociceptive effect. These results suggest that morphine treatment affects macrophage cytokine production and that tolerance affects this modulation differently.
Decrease in cAMP levels modulates adhesion to fibronectin and immunostimulatory ability of human dendritic cells
Authors: Burzyn Dalia , Jancic Carolina C , Zittermann Sandra , Keller Sarmiento María I , Fainboim Leonardo , Rosenstein Ruth E , Chuluyan H Eduardo 
Published: September 2022

AbstractThe aim of the present study was to analyze the early events elicited by tumor necrosis factor α (TNF-α) on monocyte-derived dendritic cells (moDC) adhesion to fibronectin (FN) and the involvement of cAMP in the signal transduction mechanism. The intracellular concentration of cAMP and moDC adhesion to FN decreased after TNF-α treatment. An inverted dose-dependency for TNF-α effect was observed for adhesion and cAMP levels. The presence of a phosphodiesterase (PDE) inhibitor (IBMX) and cAMP analogs (8Br-cAMP, Db-cAMP) reversed the observed TNF-α effects. The role of cAMP was analyzed further by examining the cAMP levels in nonadhered and adhered, TNF-α-treated moDC. Nonadhered moDC showed lower cAMP levels compared with adhered moDC. Furthermore, nonadhered moDC showed higher IL-12 content and allostimulatory ability compared with adhered moDC. The higher allostimulatory capacity was abolished in the presence of cAMP analogs and a PDE inhibitor. These results suggest that cAMP levels correlate with TNF-α-induced changes of moDC adhesion and allostimulatory capacity.
B cell development and proliferation of mature B cells in human fetal intestine
Authors: Golby Sarah , Hackett Maggie , Boursier Laurent , Dunn-Walters Deborah , Thiagamoorthy Sivashankari , Spencer Jo 
Published: September 2022

AbstractB cells are present in human fetal intestine from approximately 14 weeks of gestation. Here we show that this population includes mature, dividing B cells. These are large cells with dendritic processes, resembling human thymic B cells. In addition, we observed IgM+, light chain−, and CD20− cells and local expression of V pre-B, demonstrating that the human fetal intestine is a site of B cell development. Ig VHDJH gene sequencing can confirm clonal identity of B cells. Identification of the same IgVH4–34 sequence in serial sections in two fetuses confirmed local accumulation of related cells in each case. IgVH4–34 was also amplified from an additional two samples, and the D and J repertoire compared with a unique database of unselected VH4–34 genes from postnatal gut. Distinguishing characteristics of Ig λ genes in postnatal gut were also studied in the fetus. According to these parameters, fetal and postnatal B cells are unrelated.
Regulation of mediator secretion in human basophils by p38 mitogen-activated protein kinase: phosphorylation is sensitive to the effects of phosphatidylinositol 3-kinase inhibitors and calcium mobilization
Authors: Gibbs Bernhard F , Plath Katharina E S , Wolff Helmut H , Grabbe Jürgen 
Published: September 2022

AbstractAlthough human basophils modulate allergic diseases by secreting histamine, leukotriene C4, interleukin (IL)-4, and IL-13, the intermediary signals controlling the release of these mediators are poorly understood. Here, we show that p38 mitogen-activated protein kinase (MAPK) crucially affects basophil activation following stimulation with various secretagogues. Phosphorylation of p38 MAPK occurred within 5 min following anti-immunoglobulin (Ig)E stimulation, but was more rapidly activated in basophils stimulated with formyl-Met-Leu-Phe or A23187. Additionally, activation of p38 MAPK to the above stimuli was dependent on extracellular influx and intracellular mobilization of calcium. SB 203580, a specific p38 MAPK inhibitor, blocked anti-IgE-induced secretion of all basophil mediators and reduced not only p38 MAPK, but also extracellular signal-regulated kinases 1 and 2 activity, whereas the MAPK antagonist, PD 098059, did not affect p38 MAPK. IgE-dependent activation of p38 MAPK and MKK3/6 was affected by LY 294002 and wortmannin, suggesting that these kinases are targets for phosphatidylinositol 3 kinase (PI 3-K). We conclude that p38 MAPK is a pivotal regulator of basophil function downstream of PI 3-K activation and calcium mobilization.
Evidence that TNF-induced respiratory burst of adherent PMN is mediated by integrin αLβ2
Authors: Decleva Eva , Dri Pietro , Menegazzi Renzo , Busetto Sara , Cramer Rita 
Published: September 2022

AbstractPolymorphonuclear leukocytes (PMN) respond to tumor necrosis factor (TNF) with a respiratory burst (RB) only after adherence to surfaces coated with extracellular matrix proteins such as fibronectin and fibrinogen (permissive substrates) but not with others such as laminin or collagen (nonpermissive substrates). As PMN adherence to both types of surfaces is dependent on β2 integrins, we investigated the molecular basis of the different metabolic response to TNF. In particular, we evaluated the relative role of each β2 integrin (αLβ2, αMβ2, and αXβ2) in adherence and O2− production of PMN residing on fibronectin- and laminin-coated surfaces, which were considered as models of permissive and nonpermissive surfaces, respectively. By using α chain-specific monoclonal antibodies (mAb), we show that αMβ2 and αXβ2 mediate adherence to fibronectin and laminin; αLβ2 is not involved in adherence to laminin and has only a minimal contribution in adherence to fibronectin. Furthermore, production of O2− in response to TNF was induced by immobilized anti-αLβ2 but not anti-αMβ2 or anti-αXβ2 mAb. A strong correlation was also found between expression of αLβ2 and TNF-induced RB on fibronectin. Lastly, PMN responded to TNF on laminin with a RB after the inclusion of αL-specific mAb in the laminin coat. Thus, we conclude that TNF-induced RB by PMN residing on fibronectin is mediated by αLβ2 and that αMβ2 and αXβ2 are likely to play an ancillary role to the signaling activity of αLβ2 by facilitating its recruitment to sites of adherence. The nonpermissiveness of laminin appears to be a consequence of its inability to act as a ligand for αLβ2.
IL-12-dependent nuclear factor-κB activation leads to de novo synthesis and release of IL-8 and TNF-α in human neutrophils
Authors: Al-Mohanna Futwan , Saleh Soad , Parhar Ranjit S , Collison Kate 
Published: September 2022

AbstractThe cytokine interleukin (IL)-12 plays a bridging role between innate and adaptive immunity. Here, we demonstrate that treatment of neutrophils with IL-12 leads to a transient increase in intracellular-free calcium [Ca++]i levels, which is necessary for the production of reactive oxygen metabolites (ROM). This production is associated with the activation and nuclear translocation of the transcription factor nuclear factor (NF)-κB and is inhibited in the presence of the intracellular calcium chelator 1,2-bis(O-amminophenoxy) ethane-N,N-N′,N′-tetraacetic acid-acetoxymethyl ester and the ROM production inhibitor diphenyl iodonium. We show that IL-12 causes a significant increase in total mRNA levels, which appear dependent on the generated ROM. In addition IL-12 induces the de novo synthesis and production of IL-8 and tumor necrosis factor α (TNF-α) in a calcium- and ROM-dependent manner. Our data demonstrate a direct role for IL-12 in the activation of human neutrophils and suggest a ROM-dependent interplay between IL-12-induced [Ca++]i transient and the release of IL-8 and TNF-α through NF-κB activation.
Ethanol-induced inhibition of cytokine release and protein degranulation in human neutrophils
Authors: Taïeb Julien , Delarche Charlotte , Ethuin Fréderic , Selloum Saphia , Poynard Thierry , Gougerot-Pocidalo Marie-Anne , Chollet-Martin Sylvie 
Published: September 2022

AbstractEthanol impairs immune responses in humans and animal models, in vivo and in vitro. In particular, ethanol inhibits some key functions of human polymorphonuclear neutrophils (PMN). We investigated the impact of ethanol on cytokine production by highly purified PMN. In a time- and concentration-dependent manner, ethanol inhibited the production of interleukin (IL)-8 protein and mRNA and also hindered tumor necrosis factor α (TNF-α) release by modulating the expression of the TNF-α-converting enzyme involved in TNF-α shedding. This disruption of PMN cytokine release by ethanol may contribute to the increased risk of infection in alcoholic patients. Degranulation of hepatocyte growth factor (HGF) was also impaired by a clinically relevant ethanol concentration (0.8%), an action that may delay the repair of alcoholic liver damage. These findings suggest that ethanol may modulate three major cytokines involved in alcoholic liver diseases, IL-8, TNF-α, and HGF, via three different mechanisms.