bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dualism of Oxidized Lipoproteins in Provoking and Attenuating the Oxidative Burst in Macrophages: Role of Peroxisome Proliferator-Activated Receptor-γ
Authors: Fischer Barbara , von Knethen Andreas , Brüne Bernhard 
Published: April 2014

Abstract
Activation and deactivation of macrophages are of considerable importance during the development of various disease states, atherosclerosis among others. Macrophage activation is achieved by oxidized lipoproteins (oxLDL) and is determined by oxygen radical (ROS) formation. The oxidative burst was measured by flow cytometry and quantitated by oxidation of the redox-sensitive dye dichlorodihydrofluorescein diacetate. Short-time stimulation dose-dependently elicited ROS formation. Diphenylene iodonium prevented ROS formation, thus pointing to the involvement of a NAD(P)H oxidase in producing reduced oxygen species. In contrast, preincubation of macrophages with oxLDL for 16 h showed an attenuated oxidative burst upon a second contact with oxLDL. Taking into account that oxLDL is an established peroxisome proliferator-activated receptor-γ (PPARγ) agonist and considering the anti-inflammatory properties of PPARγ, we went on and showed that a PPARγ agonist such as ciglitazone attenuated ROS formation. Along that line, major lipid peroxidation products of oxLDL, such as 9- and 13-hydroxyoctadecadienoic acid, shared that performance. Supporting evidence that PPARγ activation accounted for reduced ROS generation came from studies in which proliferator-activated receptor response element decoy oligonucleotides, but not a mutated oligonucleotide, supplied in front of oxLDL delivery regained a complete oxidative burst upon cell activation. We conclude that oxLDL not only elicits an oxidative burst upon first contact, but also promotes desensitization of macrophages via activation of PPARγ. Desensitization of macrophages may have important consequences for the behavior of macrophages/foam cells in atherosclerotic lesions.
The Ubiquitously Expressed DNA-Binding Protein Late SV40 Factor Binds Ig Switch Regions and Represses Class Switching to IgA
Authors: Drouin Elise E. , Schrader Carol E. , Stavnezer Janet , Hansen Ulla 
Published: April 2014

AbstractIg heavy chain class switch recombination (CSR) determines the expression of Ig isotypes. The molecular mechanism of CSR and the factors regulating this process have remained elusive. Recombination occurs primarily within switch (S) regions, located upstream of each heavy chain gene (except Cδ). These repetitive sequences contain consensus DNA-binding sites for the DNA-binding protein late SV40 factor (LSF) (CP2/leader-binding protein-1c). In this study, we demonstrate by EMSA that purified rLSF, as well as LSF within B cell extracts, directly binds both Sμ and Sα sequences. To determine whether LSF is involved in regulating CSR, two different LSF dominant negative variants were stably expressed in the mouse B cell line I.29 μ, which can be induced to switch from IgM to IgA. Overexpression of these dominant negative LSF proteins results in decreased levels of endogenous LSF DNA-binding activity and an increase in cells undergoing CSR. Thus, LSF represses class switching to IgA. In agreement, LSF DNA-binding activity was found to decrease in whole cell extracts from splenic B cells induced to undergo class switching. To elucidate the mechanism of CSR regulation by LSF, the interactions of LSF with proteins involved in chromatin modification were tested in vitro. LSF interacts with both histone deacetylases and the corepressor Sin3A. We propose that LSF represses CSR by histone deacetylation of chromatin within S regions, thereby limiting accessibility to the switch recombination machinery.
Critical Role for Activation of Antigen-Presenting Cells in Priming of Cytotoxic T Cell Responses After Vaccination with Virus-Like Particles
Authors: Storni Tazio , Lechner Franziska , Erdmann Iris , Bächi Thomas , Jegerlehner Andrea , Dumrese Tilman , Kündig Thomas M. , Ruedl Christiane , Bachmann Martin F. 
Published: April 2014

AbstractVirus-like particles (VLPs) are known to induce strong Ab responses in the absence of adjuvants. In addition, VLPs are able to prime CTL responses in vivo. To study the efficiency of this latter process, we fused peptide p33 derived from lymphocytic choriomeningitis virus to the hepatitis B core Ag, which spontaneously assembles into VLPs (p33-VLPs). These p33-VLPs were efficiently processed in vitro and in vivo for MHC class I presentation. Nevertheless, p33-VLPs induced weak CTL responses that failed to mediate effective protection from viral challenge. However, if APCs were activated concomitantly in vivo using either anti-CD40 Abs or CpG oligonucleotides, the CTL responses induced were fully protective against infection with lymphocytic choriomeningitis virus or recombinant vaccinia virus. Moreover, these CTL responses were comparable to responses generally induced by live vaccines, because they could be measured in primary ex vivo 51Cr release assays. Thus, while VLPs alone are inefficient at inducing CTL responses, they become very powerful vaccines if applied together with substances that activate APCs.
Macrophage Effector Functions Controlled by Bruton’s Tyrosine Kinase Are More Crucial Than the Cytokine Balance of T Cell Responses for Microfilarial Clearance
Authors: Mukhopadhyay Sangita , Mohanty Madhuchhanda , Mangla Anita , George Anna , Bal Vineeta , Rath Satyajit , Ravindran Balachandran 
Published: April 2014

AbstractMacrophages from X-linked immunodeficient (xid) mice lacking functional Bruton’s tyrosine kinase (Btk) show poor NO induction and enhanced IL-12 induction, and contribute to delayed clearance of injected microfilaria (mf) in vivo. We now show that Btk is involved in other macrophage effector functions, such as bactericidal activity and secretion of proinflammatory cytokines (TNF-α, IL-1β), but not the T cell-directed cytokine IL-12. Induction of some transcriptional regulators of the NF-κB family, crucial for the expression of proinflammatory cytokines, is also poor in Btk-deficient macrophages. Thus, Btk appears to be involved in signaling for inducible effector functions, but not APC functions, in macrophages. Furthermore, adoptive transfer of T cells from mf-infected xid or wild-type mice did not alter the course of mf clearance in recipients, mf clearance was unaltered in IFN-γ-deficient mice, and improved mf clearance was seen only if greater inducibility of IL-12 was accompanied by greater NO secretion from macrophages, as seen in Ityr C.D2 mice as compared with congenic Itys BALB/c mice. Thus, delayed mf clearance in xid mice was correlated not with the high IL-12/Th1 phenotype but with low NO induction levels. Also, xid macrophages showed poor toxicity to mf in vitro as compared with wild-type macrophages. Inhibition of NO production blocked this mf cytotoxicity, and an NF-κB inhibitor blocked both NO induction and mf cytotoxicity. Thus, Btk is involved in inducing many macrophage effector functions, and delayed mf clearance seen in Btk-deficient xid mice is due to poor NO induction in macrophages, resulting in compromised microfilarial toxicity.
Recruitment Kinetics and Composition of Antibody-Secreting Cells Within the Central Nervous System Following Viral Encephalomyelitis
Authors: Tschen Shuen-Ing , Bergmann Cornelia C. , Ramakrishna Chandran , Morales Shawn , Atkinson Roscoe , Stohlman Stephen A. 
Published: April 2014

AbstractInfection by the neurotropic JHM strain of mouse hepatitis virus produces an acute demyelinating encephalomyelitis. While cellular immunity initially eliminates infectious virus, CNS viral persistence is predominantly controlled by humoral immunity. To better understand the distinct phases of immune control within the CNS, the kinetics of humoral immune responses were determined in infected mice. Early during clearance of the JHM strain of mouse hepatitis virus, only few virus-specific Ab-secreting cells (ASC) were detected in the periphery or CNS, although mature B cells and ASC without viral specificity were recruited into the CNS concomitant with T cells. Serum antiviral Ab and CNS virus-specific ASC became prominent only during final elimination of infectious virus. Virus-specific ASC peaked in lymphoid organs before the CNS, suggesting peripheral B cell priming and maturation. Following elimination of infectious virus, virus-specific ASC continued to increase within the CNS and then remained stable during persistence, in contrast to declining T cell numbers. These data comprise three novel findings. Rapid recruitment of B cells in the absence of specific Ab secretion supports a potential Ab-independent effector function involving lysis of virus-infected cells. Delayed recruitment relative to viral clearance and subsequent maintenance of a stable CNS ASC population demonstrate differential regulation of T and B lymphocytes within the infected CNS. This supports a critical role of humoral immunity in regulating viral CNS persistence. Lastly, altered antiviral ASC specificities following clearance of infectious virus suggest ongoing recruitment of peripheral memory cells and/or local B cell differentiation.
IL-13-Induced Chemokine Responses in the Lung: Role of CCR2 in the Pathogenesis of IL-13-Induced Inflammation and Remodeling
Authors: Zhu Zhou , Ma Bing , Zheng Tao , Homer Robert J. , Lee Chun Geun , Charo Israel F. , Noble Paul , Elias Jack A. 
Published: April 2014

AbstractIL-13 stimulates inflammatory and remodeling responses and contributes to the pathogenesis of human airways disorders. To further understand the cellular and molecular events that mediate these responses, we characterized the effects of IL-13 on monocyte chemotactic proteins (MCPs) and compared the tissue effects of transgenic IL-13 in mice with wild-type (+/+) and null (−/−) CCR2 loci. Transgenic IL-13 was a potent stimulator of MCP-1, -2, -3, and -5. This stimulation was not specific for MCPs because macrophage-inflammatory protein (MIP)-1α, MIP-1β, MIP-2, MIP-3α, thymus- and activation-regulated chemokine, thymus-expressed chemokine, eotaxin, eotaxin 2, macrophage-derived chemokines, and C10 were also induced. The ability of IL-13 to increase lung size, alveolar size, and lung compliance, to stimulate pulmonary inflammation, hyaluronic acid accumulation, and tissue fibrosis, and to cause respiratory failure and death were markedly decreased, whereas mucus metaplasia was not altered in CCR2−/− mice. CCR2 deficiency did not decrease the basal or IL-13-stimulated expression of target matrix metalloproteinases or cathepsins but did increase the levels of mRNA encoding α1-antitrypsin, tissue inhibitor of metalloproteinase-1, -2, and -4, and secretory leukocyte proteinase inhibitor. In addition, the levels of bioactive and total TGF-β1 were decreased in lavage fluids from IL-13 transgenic mice with −/− CCR2 loci. These studies demonstrate that IL-13 is a potent stimulator of MCPs and other CC chemokines and document the importance of MCP-CCR2 signaling in the pathogenesis of the IL-13-induced pulmonary phenotype.
Activation of Nuclear Orphan Receptor NURR1 Transcription by NF-κB and Cyclic Adenosine 5′-Monophosphate Response Element-Binding Protein in Rheumatoid Arthritis Synovial Tissue
Authors: McEvoy Alice N. , Murphy Eithne A. , Ponnio Tiia , Conneely Orla M. , Bresnihan Barry , FitzGerald Oliver , Murphy Evelyn P. 
Published: April 2014

Abstract
Modulation of the NURR subfamily of nuclear receptors may be an important mechanism regulating pathways associated with inflammatory joint disease. We examined the signaling mechanisms through which inflammatory mediators, produced by rheumatoid arthritis (RA) synovial tissue, contribute to the regulation of the NURR subfamily. Markedly enhanced expression of NURR1 is observed in synovial tissue of patients with RA compared with normal subjects. Modulation by proinflammatory mediators in primary RA and normal synoviocytes shows that PGE2, IL-1β, and TNF-α markedly enhance NURR1 mRNA and protein levels in contrast to other subfamily members, NUR77 and NOR-1. We have established that transcriptional activation of the NURR1 gene by IL-1β and TNF-α requires a proximal promoter region that contains a consensus NF-κB DNA-binding motif. IL-1β- and TNF-α-induced NF-κB binding to this site is due predominantly to p65-p50 heterodimer and p50 homodimer subunit protein complexes. We further demonstrate a direct CREB-1-dependent regulation by PGE2 situated at promoter region −171/−163. Moreover, analyses confirm the presence of CREB-1 and NF-κB p50 and p65 subunit binding to the NURR1 promoter under basal conditions in freshly explanted RA synovial tissue. In summary, enhanced NF-κB- and CREB-1-binding activity on the NURR1 promoter by inflammatory mediators delineates novel mechanisms in the regulation of NURR1 transcription. PGE2-, TNF-α-, and IL-1β-dependent stimulation of the NURR1 gene implies that NURR1 induction represents a point of convergence of at least two distinct signaling pathways, suggesting an important common role for this transcription factor in mediating multiple inflammatory signals.
Pathogenesis of Murine Experimental Allergic Rhinitis: A Study of Local and Systemic Consequences of IL-5 Deficiency
Authors: Saito Hiroko , Matsumoto Koichiro , Denburg Avram E. , Crawford Lynn , Ellis Russ , Inman Mark D. , Sehmi Roma , Takatsu Kiyoshi , Matthaei Klaus I. , Denburg Judah A. 
Published: April 2014

Abstract
Recent studies have demonstrated an important role for IL-5-dependent bone marrow eosinophil progenitors in allergic inflammation. However, studies using anti-IL-5 mAbs in human asthmatics have failed to suppress lower airway hyperresponsiveness despite suppression of eosinophilia; therefore, it is critical to examine the role of IL-5 and bone marrow responses in the pathogenesis of allergic airway disease. To do this, we studied the effects of IL-5 deficiency (IL-5−/−) on bone marrow function as well as clinical and local events, using an established experimental murine model of allergic rhinitis. Age-matched IL-5+/+ and IL-5−/− BALB/c mice were sensitized to OVA followed by 2 wk of daily OVA intranasal challenge. IL-5−/− OVA-sensitized mice had significantly higher nasal mucosal CD4+ cells and basophilic cell counts as well as nasal symptoms and histamine hyperresponsiveness than the nonsensitized group; however, there was no eosinophilia in either nasal mucosa or bone marrow; significantly lower numbers of eosinophil/basophil CFU and maturing CFU eosinophils in the presence of recombinant mouse IL-5 in vitro; and significantly lower expression of IL-5Rα on bone marrow CD34+CD45+ progenitor cells in IL-5−/− mice. These findings suggest that IL-5 is required for normal bone marrow eosinophilopoiesis, in response to specific Ag sensitization, during the development of experimental allergic rhinitis. However, the results also suggest that suppression of the IL-5-eosinophil pathway in this model of allergic rhinitis may not completely suppress clinical symptoms or nasal histamine hyperresponsiveness, because of the existence of other cytokine-progenitor pathways that may induce and maintain the presence of other inflammatory cell populations.
Antimicrobial Peptides Initiate IL-1β Posttranslational Processing: A Novel Role Beyond Innate Immunity
Authors: Perregaux David G. , Bhavsar Kanan , Contillo Len , Shi Jishu , Gabel Christopher A. 
Published: April 2014

AbstractHuman monocytes stimulated with LPS produce large quantities of prointerleukin-1β, but little of this cytokine product is released extracellularly as the mature biologically active species. To demonstrate efficient proteolytic cleavage and export, cytokine-producing cells require a secondary effector stimulus. In an attempt to identify agents that may serve as initiators of IL-1β posttranslational processing in vivo, LPS-activated human monocytes were treated with several individual antimicrobial peptides. Two peptides derived from porcine neutrophils, protegrin (PTG)-1 and PTG-3, promoted rapid and efficient release of mature IL-1β. The PTG-mediated response engaged a mechanism similar to that initiated by extracellular ATP acting via the P2X7 receptor. Thus, both processes were disrupted by a caspase inhibitor, both were sensitive to ethacrynic acid and CP-424,174, two pharmacological agents that suppress posttranslational processing, and both were negated by elevation of extracellular potassium. Moreover, the PTGs, like ATP, promoted a dramatic change in monocyte morphology and a loss of membrane latency. The PTG response was concentration dependent and was influenced profoundly by components within the culture medium. In contrast, porcine neutrophil antimicrobial peptides PR-26 and PR-39 did not initiate IL-1β posttranslational processing. The human defensin HNP-1 and the frog peptide magainin 1 elicited export of 17-kDa IL-1β, but these agents were less efficient than PTGs. As a result of this ability to promote release of potent proinflammatory cytokines such as IL-1β, select antimicrobial peptides may possess important immunomodulatory functions that extend beyond innate immunity.
TheHelicobacter pyloriBlood Group Antigen-Binding Adhesin Facilitates Bacterial Colonization and Augments a Nonspecific Immune Response
Authors: Rad Roland , Gerhard Markus , Lang Roland , Schöniger Martin , Rösch Thomas , Schepp Wolfgang , Becker Ingrid , Wagner Hermann , Prinz Christian 
Published: April 2014

AbstractPresence of the Helicobacter pylori adherence factor blood group Ag-binding adhesin (BabA; binding to Lewisb (Leb)) is associated with ulcer disease, adenocarcinoma, and precancerous lesions. The importance of BabA for bacterial colonization and the inflammatory response is unknown. A total of 141 antral biopsies from H. pylori-infected patients were assessed in regard to the degree of granulocytic (G0°–G3°) and lymphocytic (L1°–L3°) infiltration. DNA genotypes of babA2 (the transcriptionally active gene of BabA), cagA, and vacAs1/2 were determined by PCR. Colonization density and Leb status on gastric epithelial cells were determined by immunohistochemistry. Real-time quantitative (TaqMan) RT-PCR determined mRNA expression of IL-8, TNF -α, and the Th1 markers IFN-γ and the IL-12R β2 chain. A total of 91% of infected patients were Leb positive. The vacAs1+/cagA+ strains harboring babA2 showed significantly higher levels of granulocytic infiltration, bacterial colonization, and IL-8 mRNA than vacAs1+/cagA+ strains lacking babA2. IL-8 mRNA and protein production by KATO III cells in vitro increased dose dependently with addition of different numbers of type 1 strains (G27 and 2808 strains, 0.1–20 bacteria/cell). The mRNA expression of TNF-α, IFN-γ, and IL-12R β2 was higher in H. pylori-positive patients than in controls, but it did not differ significantly between patients infected with different strain types. These data suggest that BabA facilitates colonization of H. pylori and thereby increases IL-8 response, resulting in enhanced mucosal inflammation. Infection with strains harboring BabA thereby augment a nonspecific immune response, whereas the Th1 response toward H. pylori appears to be independent of BabA, cytotoxin-associated gene A, or vacuolating cytotoxin.
A Novel Susceptibility Locus On Chromosome 2 in the (New Zealand Black × New Zealand White)F1 Hybrid Mouse Model of Systemic Lupus Erythematosus
Authors: Rahman Ziaur SM. , Tin Soe-Kyaw , Buenaventura Pia-Nina L. , Ho Chiu-Han , Yap Eric P. H. , Yong Rita Y. Y. , Koh Dow-Rhoon 
Published: April 2014

AbstractSystemic lupus erythematosus (SLE) is inherited as a complex polygenic trait. (New Zealand Black (NZB) × New Zealand White (NZW)) F1 hybrid mice develop symptoms that remarkably resemble human SLE, but (NZB × PL/J)F1 hybrids do not develop lupus. Our study was conducted using (NZW × PL/J)F1 × NZB (BWP) mice to determine the effects of the PL/J and the NZW genome on disease. Forty-five percent of BWP female mice had significant proteinuria and 25% died before 12 mo of age compared with (NZB × NZW)F1 mice in which &gt;90% developed severe renal disease and died before 12 mo. The analysis of BWP mice revealed a novel locus (χ2 = 25.0; p &lt; 1 × 10−6; log of likelihood = 6.6 for mortality) designated Wbw1 on chromosome 2, which apparently plays an important role in the development of the disease. We also observed that both H-2 class II (the u haplotype) and TNF-α (TNFz allele) appear to contribute to the disease. A suggestive linkage to proteinuria and death was found for an NZW allele (designated Wbw2) telomeric to the H-2 locus. The NZW allele that overlaps with the previously described locus Sle1c at the telomeric part of chromosome 1 was associated with antinuclear autoantibody production in the present study. Furthermore, the previously identified Sle and Lbw susceptibility loci were associated with an increased incidence of disease. Thus, multiple NZW alleles including the Wbw1 allele discovered in this study contribute to disease induction, in conjunction with the NZB genome, and the PL/J genome appears to be protective.
TNF-TNFR2 Interactions Are Critical for the Development of Intestinal Graft-Versus-Host Disease in MHC Class II-Disparate (C57BL/6J→C57BL/6J × bm12)F1 Mice
Authors: Brown Geri R. , Lee Ed , Thiele Dwain L. 
Published: April 2014

AbstractTNF-TNFR2 interactions promote MHC class II-stimulated alloresponses while TNF-TNFR1 interactions promote MHC class I-stimulated alloresponses. The present studies were designed to evaluate whether TNF-TNFR2 interactions were involved in the in vivo generation of CD4+ T cell-mediated intestinal graft-versus-host disease (GVHD) in the (C57BL/6J (hereafter called B6)→B6 × B6.C-H-2bm12 (bm12))F1 GVHD model. Briefly, 5 × 106 splenic CD4+ T lymphocytes from B6.TNFR2−/− or control B6 mice were transferred with 1–2 × 106 T cell-depleted B6 bone marrow cells (BMC) to irradiated MHC class II-disparate (bm12 × B6)F1 mice. Weight loss, intestinal inflammation, and the surface expression of CD45RB (memory marker) on intestinal and splenic lymphocytes were assessed. IL-2 and IFN-α mRNA levels in intestinal lymphocytes were assessed by nuclease protection assays. A significant reduction in weight loss and intestinal inflammation was observed in recipients of the TNFR2−/−CD4+ SpC. Similarly, a significant decrease was noted in T cell numbers and in CD45RBlow (activated/memory) expression on intestinal but not CD4+ T cells in recipients of TNFR2−/−CD4+ spleen cells. IL-2 and IFN-α mRNA levels were reduced in the intestine in the recipients of TNFR2−/− splenic CD4+ T cells. These results indicate that TNF-TNFR2 interactions are important for the development of intestinal inflammation and activation/differentiation of Th1 cytokine responses by intestinal lymphocytes in MHC class II-disparate GVHD while playing an insignificant role in donor T cell activation in the spleen.