bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differences in mannose receptor-mediated uptake of lipoarabinomannan from virulent and attenuated strains of Mycobacterium tuberculosis by human macrophages.
Authors: Schlesinger L S , Kaufman T M , Iyer S , Hull S R , Marchiando L K 
Published: December 2022

Abstract
Phagocytosis of the virulent Erdman and H37Rv strains of Mycobacterium tuberculosis, but not that of the attenuated H37Ra strain, by human macrophages is mediated by the mannose receptor (MR) in addition to complement receptors. We have recently determined that a major capsular lipoglycan, lipoarabinomannan (LAM), from the Erdman strain serves as a ligand for the MR during phagocytosis of bacteria. In this study we directly compare uptake of Erdman, H37Rv, and H37Ra LAM by human macrophages and assess the relative contribution of the MR in this process. Microspheres coated with LAM served as model phagocytic particles for studies of LAM as a capsular ligand. Uptake (37 degrees C) of LAM microspheres by monocyte-derived macrophages was greatest for Erdman LAM and intermediate for H37Rv and H37Ra LAM compared with that of buffer microspheres or microspheres coated with LAM from a nontuberculosis strain of mycobacterium (AraLAM). Inhibition of microsphere uptake in the presence of mannan or mannose-BSA was highest for Erdman LAM (75 +/- 8 and 50 +/- 7%, respectively) and H37Rv LAM (57 +/- 13 and 21 +/- 5%, respectively) relative to H37Ra LAM (36 +/- 16 and 22 +/- 11 %, respectively). Inhibition of microsphere uptake in the presence of anti-MR Ab followed a similar pattern: Erdman LAM (80 +/- 9%) &gt; H37Rv LAM (53 +/- 1%) &gt; H37Ra LAM (26 +/- 12%). Attachment (4 degrees C) of microspheres coated with Erdman LAM, H37Rv LAM, and H37Ra LAM was enhanced 12-, 5-, and 4-fold, respectively, compared with that of microspheres coated with AraLAM, and mannose-BSA inhibited attachment of these microspheres by 82 +/- 7, 69 +/- 8, and 12 +/- 17%. Galactose-BSA did not inhibit attachment of any LAM microsphere groups. Chromatographic analyses of mild acid hydrolysates of LAM from Erdman, H37Rv, and H37Ra all revealed the major terminal dimannosyl units. These studies demonstrate differences in the ability of LAM from different M. tuberculosis strains to mediate adherence to macrophages and to serve as ligands for the macrophage MR despite the presence of terminal dimannosyl units. Thus, these studies point toward other subtle structural alterations in LAM among strains that influence initial interactions with human phagocytes.
The role of P-selectin and ICAM-1 in acute lung injury as determined using blocking antibodies and mutant mice.
Authors: Doerschuk C M , Quinlan W M , Doyle N A , Bullard D C , Vestweber D , Jones M L , Takei F , Ward P A , Beaudet A L 
Published: December 2022

Abstract
Cobra venom factor (CVF) induces lung injury through oxidant- and neutrophil-dependent mechanisms. Adhesion molecules, particularly L-selectin, P-selectin, CD11/CD18, and ICAM-1, are required for full expression of injury in rats. This study compared the roles of P-selectin and ICAM-1 using either mutant mice or blocking Abs. Mice deficient in either P-selectin, ICAM-1, or both adhesion molecules were compared with wild-type mice. Wild-type and single mutant mice were given Abs against murine P-selectin or ICAM-1. CVF was injected i.v., and neutrophil sequestration and extravascular albumin were measured 30 min later. Neither P-selectin, ICAM-1, nor P-selectin/ICAM-1 double mutants showed a reduction in neutrophil sequestration or lung injury when compared with wild-type mice. Anti-P-selectin Abs inhibited both sequestration and injury in wild-type mice by 57% and 60%, respectively, but had no effect in P-selectin mutants. Similar results were found using anti-ICAM-1 Ab in wild-type mice (78% inhibition of sequestration and 88% inhibition of injury) and ICAM-1 mutant mice (no reduction). These results suggest that the apparent role of these molecules in CVF-induced lung injury depends on the method used to block function. When studied using blocking Abs, both P-selectin and ICAM-1 were required for neutrophil sequestration and lung injury, while neither played a role singly or together when studied using mice with genetic deletions. Abs may inhibit neutrophil sequestration and lung injury through mechanisms other than simply adhesion blockade, or mutant mice may utilize alternative adhesion pathways.
Mechanisms of smokeless tobacco-induced oral mucosa inflammation: role of bradykinin.
Authors: Gao X P , Vishwanatha J K , Conlon J M , Olopade C O , Rubinstein I 
Published: December 2022

Abstract
The purpose of this study was to determine whether an aqueous extract of smokeless tobacco (moist snuff) increases clearance of macromolecules from postcapillary venules in the in situ oral mucosa and, if so, whether bradykinin mediated this response. Using intravital microscopy, we found that 20-min suffusion of the extract elicited significant concentration-dependent leaky site formation and increase in clearance of FITC-dextran (molecular mass, 70 kDa) from the hamster cheek pouch (p &lt; 0.05). These responses were associated with a significant increase in bradykinin-like immunoreactivity in the suffusate. Smokeless tobacco extract-induced leaky site formation and increase in clearance of FITC-dextran were significantly attenuated by NPC 17647 and Hoe 140 (p &lt; 0.05), two bradykinin B2 receptor antagonists, but not by desArg9,[Leu8]bradykinin, a bradykinin B1 receptor antagonist. Both bradykinin B2 receptor antagonists had no significant effects on adenosine-induced responses. Indomethacin had no significant effects on smokeless tobacco extract-induced responses. Exposure to smokeless tobacco extract was associated with a significant decrease in angiotensin I-converting enzyme activity and a small, but significant, increase in neutral endopeptidase 24.11 activity in the cheek pouch, two peptidases widely distributed in the microcirculation that cleave and inactivate bradykinin (p &lt; 0.05). Overall, these data suggest that smokeless tobacco elicits plasma exudation in the oral mucosa in vivo in a specific fashion, and that this response is mediated by bradykinin.
Identification and regulation of protein kinase C-delta in human neutrophils.
Authors: Kent J D , Sergeant S , Burns D J , McPhail L C 
Published: December 2022

Abstract
The intracellular mechanisms that regulate the function of human neutrophils are not well understood. Receptor-initiated signaling events result in the production of several second messengers (e.g., Ca2+, diacylglycerol, phosphatidic acid, and arachidonic acid) with the potential to activate members of the protein kinase C (PKC) family of signaling enzymes. The mixture of second messenger signaling molecules produced usually varies, depending on the particular receptor engaged. Previous work suggests that PKC has complex regulatory effects on neutrophil function. This may be due to the presence of multiple isoforms of the enzyme family, responding differentially to the second messengers produced. In studies to identify the PKC isoforms present in human neutrophils, we discovered the presence of the PKC isoform delta in these cells. Like other previously identified isoforms (alpha, beta I, beta II, and zeta), delta is a cytosolic enzyme in unstimulated neutrophils and partially translocates to membrane-containing fractions in cells stimulated by either the PKC activator PMA or the chemoattractant FMLP. Partial purification of cytosolic PKC gave two peaks of activity. The beta isoforms predominated in peak I, while the delta isoform predominated in peak II. The identification of delta indicates that neutrophils contain at least one member of the Ca(2+)-independent, diacylglycerol-dependent subfamily of PKC isoforms. Thus, this isoform may participate in Ca(2+)-independent, but diacylglycerol-dependent signaling events in these cells.
Defective Fc gamma RII gene expression in macrophages of NOD mice: genetic linkage with up-regulation of IgG1 and IgG2b in serum.
Authors: Luan J J , Monteiro R C , Sautès C , Fluteau G , Eloy L , Fridman W H , Bach J F , Garchon H J 
Published: December 2022

Abstract
A quantitative trait locus for increased IgG serum levels in the NOD mouse strain was mapped to distal chromosome 1, close to the fcgr2 locus encoding the low-affinity type II receptor for the Fc portion of IgG (Fc gamma RII). Expression of membrane-inserted (b2) and soluble (b3) isoforms of Fc gamma RII was strongly decreased in macrophages of NOD compared with C57BL/6 (B6) mice. In contrast, B cell-specific (Fc gamma RIIb1) isoform was only slightly decreased and Fc gamma RIII was not altered. This Fc gamma RII regulatory defect was cis-encoded by fcgr2 or by a closely linked locus, occurred at the mRNA level, and was associated with multiple mutations in the fcgr2 gene promoter. In relation with this defect, binding of IgG1- and IgG2b- but not IgG2a-opsonized RBC by macrophages of NOD and congenic B6.NOD-fcgr2 mice was severely impaired, but was normal in macrophages of NOD.B6-fcgr2 congenic mice, indicating that Fc gamma RII plays a nondispensable role in binding of IgG1 and IgG2b isotypes. Likewise, serum levels of IgG1 and IgG2b but not IgG2a were up-regulated in NOD compared with NOD.B6-fcgr2 congenic mice. These findings indicate that macrophage Fc gamma RII may regulate serum IgG1 and IgG2b through their catabolism, and validate the NOD strain as a model to investigate the functions of Fc gamma RII isoforms.
Prevention of autoimmune diabetes by linomide in nonobese diabetic (NOD) mice is associated with up-regulation of the TCR-mediated activation of p21(ras).
Authors: Rapoport M J , Weiss L , Mor A , Bistritzer T , Ramot Y , Slavin S 
Published: December 2022

Abstract
Oral therapy with linomide protects prediabetic nonobese diabetic (NOD) mice from insulin-dependent diabetes mellitus. The mechanisms by which linomide exerts its protective effect are not fully understood. A decreased TCR-mediated activity of the GTP-GDP binding p21(ras) proto-oncogene is associated with prediabetes in NOD mice. However, the role of this signal transduction defect in the pathogenesis of autoimmune diabetes is not known. The TCR-mediated and protein kinase C-induced activations of p21(ras) were determined in mononuclear cells from lymph nodes of linomide-treated and untreated prediabetic NOD mice. TCR cross-linking by Con A induced an increase of 13 +/- 6.8% and a decrease of 0.8 +/- 1.8% in p21(ras) activity in the linomide-treated group and the untreated controls, respectively. Cell stimulation with PMA resulted in a 15 +/- 2% increase in p21(ras) activity in the linomide-treated mice and a 10 +/- 11.4% decrease in the untreated mice. Protein levels of p21(ras) and its regulatory elements, the GTPase-activating protein and the guanine nucleotide-releasing factor, mSOS, were comparable in both groups. We, therefore, conclude that prevention of autoimmune diabetes by linomide is associated with up-regulation of the p21(ras) T cell signal transduction defect in NOD mice.
IL-4 neutralization or TNF-alpha treatment ameliorate disease by an intracellular pathogen in IFN-gamma receptor-deficient mice.
Authors: Szalay G , Ladel C H , Blum C , Kaufmann S H 
Published: December 2022

Abstract
Successful control of infectious disease depends on aquisition of an appropriate protective immune response. IFN-gamma, first produced by NK cells and then by Th1 cells, is central to acquired resistance against intracellular bacteria, including Listeria monocytogenes. In contrast, IL-4 is not generated to a measurable degree. Here we show that IL-4 is produced during listeriosis by IFN-gamma receptor gene disruption (IFN-gammaR(-/-)) mutant mice. Production of TNF was diminished, whereas IL-12 production was virtually unchanged in these mutants. Neutralization of IL-4 with anti-IL-4 mAb, as well as TNF-alpha reconstitution with rTNF-alpha, ameliorated listeriosis. These findings demonstrate the detrimental effects of IL-4 in listeriosis independent of IFN-gamma down-regulation and document the far-reaching consequences of a single cytokine deficiency on other cytokines. In cases where the primary gene defect cannot be restored, precise identification of secondary effects will promote rational immunotherapy based on neutralization or reconstitution of secondary immune deviations.
Modulation of HLA-DQ binding properties by differences in class II dimer stability and pH-dependent peptide interactions.
Authors: Buckner J , Kwok W W , Nepom B , Nepom G T 
Published: December 2022

Abstract
Intermolecular interactions between peptides and class II molecules intracellularly are likely to be influenced by different pH conditions in different endosomal compartments. We compared the pH-dependent binding of peptides to HLA-DQ alleles 3.1 and 3.2, two well-studied human class II molecules with limited structural variability but different genetic associations with autoimmune diseases. Binding of the "promiscuous" binding peptide 34P3A as well as that of several allele-specific peptides were optimal for DQ3.2 at relatively acidic pH, compared with DQ3.1, with a pH optimum for DQ3.2 at pH 5.5 and for DQ3.1 at pH 6.5. A specific polymorphism at residue 57 of the DQ molecule accounted for some, but not all, of this difference. When the intrinsic stability of the class II dimer was assessed using partially denaturing gel electrophoresis after incubation at different pH, the DQ3.2 molecule demonstrated relative instability at neutral pH compared with DQ3.1, again suggesting a preference for peptide binding at relatively acidic conditions for HLA-DQ3.2. Interestingly, this preference for binding at acidic pH was not found for a class II-associated invariant chain peptide. Intrinsic alphabeta dimer stability and the pH optima for peptide binding studied in this report are likely to be significant determinants for allelic differences in DQ binding profiles in vivo.
Altered orientation of streptococcal superantigen (SSA) on HLA-DR1 allows unconventional regions to contribute to SSA Vbeta specificity.
Authors: Stevens K R , Van M , Lamphear J G , Rich R R 
Published: December 2022

Abstract
Crystallographic studies reveal even distantly related bacterial superantigens (SAg) to adopt a common structural topology. Mutational analyses confirm that this shared folding pattern often confers a conserved function to analogous residues in different SAg, albeit with specificities for particular TCR or MHC class II molecules. It was thus surprising that the streptococcal SAg SSA differed from related SAg in the location of its Vbeta-determining residues. Because it seemed unlikely that SSA would deviate significantly from an SAg-like topology, we hypothesized that variations in SSA Vbeta-determining regions might result from differences in SSA-MHC class II interactions relative to other SAg during SSA presentation to the TCR. Comparison of the DR1-binding properties of SSA with its closest homologue SEB found different amino acid positions within SAg primary sequences to contribute to SSA-DR1 and SEB-DR1 interactions, and suggested that SSA bound DR1 with an altered orientation relative to SEB. The common involvement of DR1 alpha39K, however, predicted that the two SAg bound overlapping sites on DR1. Nevertheless, SSA and SEB did not effectively cross-compete for DR1 binding and had opposite patterns of DR1-binding affinity in the presence of distinct DR1-expressing cell lines. The data thus suggest that SSA and SEB bind not only with different orientations on DR1, but may bind preferentially to distinct DR1 subsets delineated by cell-specific factors. Differences in orientation of SSA on DR1 and/or interaction of SSA with particular DR1 subsets may explain why unconventional regions influence SSA TCR Vbeta specificity.
The roles of CD11/CD18 and ICAM-1 in acute Pseudomonas aeruginosa-induced pneumonia in mice.
Authors: Qin L , Quinlan W M , Doyle N A , Graham L , Sligh J E , Takei F , Beaudet A L , Doerschuk C M 
Published: December 2022

Abstract
Neutrophil accumulation in response to Pseudomonas aeruginosa in the lungs is mediated through CD11/CD18. This study determined the roles of CD11a, CD11b, and intercellular adhesion molecule (ICAM)-1 in P. aeruginosa-induced pneumonia and compared the function of ICAM-1 using Abs or ICAM-1 mutant mice. Anesthetized BALB/c mice pretreated with either Abs against CD11a, CD11b, ICAM-1, or rat IgG received intratracheal instillation of P. aeruginosa for 4 h. In other studies, ICAM-1 mutant and wild-type mice received either anti-ICAM-1 Ab or rat IgG followed by instillation of P. aeruginosa. The data show that Abs against CD11a, CD11b, and ICAM-1 in BALB/c mice inhibited neutrophil emigration by 79, 81, and 56%, respectively. ICAM-1 mutant mice showed no inhibition of neutrophil emigration compared with wild-type mice. Pretreatment with anti-ICAM-1 Ab inhibited neutrophil emigration in wild-type (129/SvxC57) mice by 67% but had no effect in ICAM-1 mutant mice, suggesting that the Ab was acting specifically through recognition of its Ag. We conclude that CD11a and CD11b are required for neutrophil emigration. The observed function of ICAM-1 varies depending on the method by which it is inhibited. Abs may overestimate function by altering other cellular functions or mutant mice may develop alternative pathways of emigration.
A differential role for cell shape in neutrophil tethering and rolling on endothelial selectins under flow.
Authors: Finger E B , Bruehl R E , Bainton D F , Springer T A 
Published: December 2022

Abstract
We investigated the role of neutrophil microvilli in interactions with E-selectin and P-selectin in hydrodynamic shear flow by disruption with cytochalasin B, hypotonic swelling, and chilling. Cytochalasin B only marginally reduced microvilli numbers (from 30 +/- 6 to 16 +/- 6 per cell perimeter, p &lt; 0.005) as shown by electron microscopy, completely disrupted tethering in shear flow to E-selectin and P-selectin, increased the strength of rolling adhesions on E-selectin and P-selectin, and increased cell deformability in shear flow with a likely increase in the area of cell:substrate contact. Hypoosmotic swelling markedly reduced microvilli number (to 6 +/- 5 per perimeter, p &lt; 0.005), almost completely inhibited tethering on E- and P-selectin, and increased the strength of rolling adhesions on P-selectin but not on E-selectin. Chilling almost completely abolished microvilli (to 3 +/- 3 per perimeter, p &lt; 0.005), but pseudopod-like structures were present, and had little effect on tethering in flow. Immunogold labeling of L-selectin, which is normally clustered on tips of microvilli, showed that in the absence of microvilli it remained in small clusters. Our studies show that alterations in cell morphology and viscoelasticity can have opposing effects on tethering and rolling, showing that they are independently regulatable. Furthermore, our results suggest that the association of molecules that mediate rolling with microvilli tips may be important not just to enhance presentation, but for other functions such as to promote resistance to extraction from the membrane or cooperative interactions among clustered receptors.
Cross-linking of intercellular adhesion molecule 1 (CD54) induces AP-1 activation and IL-1beta transcription.
Authors: Koyama Y , Tanaka Y , Saito K , Abe M , Nakatsuka K , Morimoto I , Auron P E , Eto S 
Published: December 2022

Abstract
Leukocytes adhere to target cells through their integrins and play a crucial role in self-defense, inflammation, and differentiation. Intercellular adhesion molecule-1 (ICAM-1; CD54) is a representative ligand for integrins and is expressed on many cell types, some of which are targets for leukocyte adhesion. Recent studies suggest that adhesion molecules function not only as a cellular glue, but also as a signal transducer. However, it remains to be clearly defined whether engagement of ICAM-1 is able to induce activation signals in target cells. In rheumatoid synovium, synovial cells are known to express abundant ICAM-1 and produce multiple inflammatory cytokines, such as IL-1beta. In this study, we provide the first evidence that ICAM-1 engagement induces activation of the transcription factor AP-1 and transcription of the IL-1beta gene using a specific Ab to cross-link ICAM-1 on a rheumatoid synovial cell line (E11 cells). This evidence includes ICAM-1 cross-linking-dependent induction of 1) in situ IL-1beta transcription and protein synthesis, 2) transiently transfected chloramphenicol acetyltransferase (CAT) reporter plasmids containing both the IL-1beta LPS-responsive enhancer (between -3134 and -2729) as well as multiple copies of an AP-1 site from this enhancer (between -3117 and -3111), and 3) the binding of a Jun/Fos family complex to this AP-1 site. Thus, ICAM-1 not only functions as a glue for integrin binding, but also as a transducer for AP-1 activation signals important for IL-1beta gene transcription.
Chemical characteristics of Staphylococcus aureus molecules that have CD14-dependent cell-stimulating activity.
Authors: Kusunoki T , Wright S D 
Published: December 2022

Abstract
We have previously shown that Staphylococcus aureus contains molecules that bind CD14 and induce cellular responses. We have partially purified this activity and named the product active fraction (AF). Here, we further explore the chemical characteristics of AF. We show that 1) the activity is sensitive to base and hydrofluoric acid hydrolysis; 2) AF binds to Mono Q, indicating that it is negatively charged; 3) most activity in AF runs as a large species in aqueous buffer, but a small proportion runs with a size of &lt;15 kDa by gel chromatography; and 4) native PAGE of AF yields a band of high apparent m.w., and SDS-PAGE yields a ladder of bands of lower apparent m.w. These data suggest that AF is a mixture of heterogeneous amphiphilic molecules that form tight micelles. These characteristics are shared by LPS, suggesting that AF has both functional and structural similarity to LPS. S. aureus cell wall has been shown to stimulate cells in a CD14-dependent fashion, and peptidoglycan (PGN) has thus been described as a ligand for membrane CD14. However, we found that the ability of S. aureus cell wall to stimulate CD14-bearing monocytes was enhanced by preincubation with soluble CD14 (sCD14). Upon treatment with sCD14, the cell-stimulating activity appeared predominantly in the supernatant, not in the insoluble PGN pellet. These findings are not consistent with a direct interaction of membrane CD14 with insoluble PGN. They suggest, rather, that the activity of cell wall may be caused by a sCD14-binding molecule that associates noncovalently with PGN.