bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell Intrinsic TGF-β1 Regulation of B Cells
Authors: Gros Marilyn J. , Naquet Philippe , Guinamard Rodolphe R. 
Published: April 2014

AbstractTGF-β family cytokines play multiple roles in immune responses. TGF-β1-null mice suffer from multi-organ infiltration that leads to their premature death. T cells play a central role in the TGF-β1 phenotype, as deficiency of TGF-β1 only in T cells reproduces the lethal phenotype. Although it is known that TGF-β1 controls B cells isotype switch and homeostasis, the source responsible for this control has not been characterized. Because of the major role that T cells play in regulating B cell responses, we addressed the T cell dependency of the TGF-β1 control of B cells. The analysis of T cell-deficient, TGF-β1 knockout mice and the production of chimeras in which B but not T cells lacked TGF-β1 allowed us to show that B cells are controlled in part by cell autonomous production of TGF-β1.
Molecular Basis of the Dual Functions of 2B4 (CD244)
Authors: Chlewicki Lukasz K. , Velikovsky C. Alejandro , Balakrishnan Vamsi , Mariuzza Roy A. , Kumar Vinay 
Published: April 2014

Abstract2B4 belongs to the CD2 family of molecules and is expressed on all NK, γδ, and memory CD8+ (αβ) T cells. The murine NK receptor 2B4 exhibits both inhibitory and activating functions, whereas human 2B4 has been reported to be an activating molecule. How murine 2B4 can act both as an activating and inhibitory receptor and what distinguishes its function from human 2B4 have remained largely unknown. We use here a model system that allows the study of human and murine 2B4 under identical and controlled conditions. These studies reveal that both human and mouse 2B4 can activate or inhibit NK cells. We show here that the level of 2B4 expression and the degree of 2B4 cross-linking play a significant role in the regulation of signaling lymphocyte activation molecule-associated protein-mediated activation by 2B4. A high level of 2B4 expression, heavy cross-linking, and relative paucity of signaling lymphocyte activation molecule-associated protein promote inhibitory function. Our studies demonstrate how a single receptor can have opposing function depending on the degree of receptor expression, extent of its ligation, and the relative abundance of certain adaptor molecules. Because the levels of 2B4 and CD48 are dynamically regulated, these findings have implications for the regulation of NK cell function.
NK Cell Protease Granzyme M Targets α-Tubulin and Disorganizes the Microtubule Network
Authors: Bovenschen Niels , de Koning Pieter J. A. , Quadir Razi , Broekhuizen Roel , Damen J. Mirjam A. , Froelich Christopher J. , Slijper Monique , Kummer J. Alain 
Published: April 2014

Abstract
Serine protease granzyme M (GrM) is highly expressed in the cytolytic granules of NK cells, which eliminate virus-infected cells and tumor cells. The molecular mechanisms by which GrM induces cell death, however, remain poorly understood. In this study we used a proteomic approach to scan the native proteome of human tumor cells for intracellular substrates of GrM. Among other findings, this approach revealed several components of the cytoskeleton. GrM directly and efficiently cleaved the actin-plasma membrane linker ezrin and the microtubule component α-tubulin by using purified proteins, tumor cell lysates, and tumor cells undergoing cell death induced by perforin and GrM. These cleavage events occurred independently of caspases or other cysteine proteases. Kinetically, α-tubulin was more efficiently cleaved by GrM as compared with ezrin. Direct α-tubulin proteolysis by GrM is complex and occurs at multiple cleavage sites, one of them being Leu at position 269. GrM disturbed tubulin polymerization dynamics in vitro and induced microtubule network disorganization in tumor cells in vivo. We conclude that GrM targets major components of the cytoskeleton that likely contribute to NK cell-induced cell death.
Platelet-Activating Factor-Mediated Endosome Formation Causes Membrane Translocation of p67phox and p40phox That Requires Recruitment and Activation of p38 MAPK, Rab5a, and Phosphatidylinositol 3-Kinase in Human Neutrophils
Authors: McLaughlin Nathan J. D. , Banerjee Anirban , Khan Samina Y. , Lieber Janet L. , Kelher Marguerite R. , Gamboni-Robertson Fabia , Sheppard Forest R. , Moore Ernest E. , Mierau Gary W. , Elzi David J. , Silliman Christopher C. 
Published: April 2014

Abstract
Neutrophils (polymorphonuclear leukocytes, PMNs) are vital to innate immunity and receive proinflammatory signals that activate G protein-coupled receptors (GPCRs). Because GPCRs transduce signals through clathrin-mediated endocytosis (CME), we hypothesized that platelet-activating factor (PAF), an effective chemoattractant that primes the PMN oxidase, would signal through CME, specifically via dynamin-2 activation and endosomal formation resulting in membrane translocation of cytosolic phagocyte oxidase (phox) proteins. PMNs were incubated with buffer or 2 μM PAF for 1–3 min, and in some cases activated with PMA, and O2− was measured, whole-cell lysates and subcellular fractions were prepared, or the PMNs were fixed onto slides for digital or electron microscopy. PAF caused activation of dynamin-2, resulting in endosomal formation that required PI3K and contained early endosomal Ag-1 (EEA-1) and Rab5a. The apoptosis signal-regulating kinase-1/MAPK kinase-3/p38 MAPK signalosome assembled on Rab5a and phosphorylated EEA-1 and Rab GDP dissociation inhibitor, with the latter causing Rab5a activation. Electron microscopy demonstrated that PAF caused two distinct sites for activation of p38 MAPK. EEA-1 provided a scaffold for recruitment of the p40phox-p67phox complex and PI3K-dependent Akt1 phosphorylation of these two phox proteins. PAF induced membrane translocation of p40phox-p67phox localizing to gp91phox, which was PI3K-, but not p47phox-, dependent. In conclusion, PAF transduces signals through CME, and such GPCR signaling may allow for pharmacological manipulation of these cells to decrease PMN-mediated acute organ injury.
Two Different Transcription Factors Discriminate the −315C&gt;T Polymorphism of theFcεRIα Gene: Binding of Sp1 to −315C and of a High Mobility Group-Related Molecule to −315T
Authors: Kanada Shunsuke , Nakano Nobuhiro , Potaczek Daniel P. , Maeda Keiko , Shimokawa Naomi , Niwa Yusuke , Fukai Tatsuo , Sanak Marek , Szczeklik Andrew , Yagita Hideo , Okumura Ko , Ogawa Hideoki , Nishiyama Chiharu 
Published: April 2014

AbstractThe α-chain is a specific component of FcεRI, which is essential for the cell surface expression of FcεRI and the binding of IgE. Recently, two single nucleotide polymorphisms (SNPs) in the α-chain promoter, −315C&gt;T and −66T&gt;C, have been shown by statistic studies to associate with allergic diseases. The effect of −66 SNP on GATA-1-mediated promoter activity has been already indicated. In the present study, to investigate roles of the −315 SNP on the α-chain promoter functions, the transcription activity was evaluated by reporter assay. The α-chain promoter carrying −315T (minor allele) possessed significantly higher transcriptional activity than that of −315C (major allele). EMSA indicated that the transcription factor Sp1, but not Myc-associated zinc finger protein (MAZ), was bound to the −315C allele probe and that a transcription factor belonging to a high mobility group-family bound to the −315T allele probe. The chromatin immunoprecipitation assay suggested that high mobility group 1, 2, and Sp1 bound around −315 of FcεRIα genomic DNA in vivo in the human basophil cell line KU812 with −315C/T and in human peripheral blood basophils with −315C/C, respectively. When cell surface expression level of FcεRI on basophils was analyzed by flow cytometry, basophils from individuals carrying −315T allele expressed significantly higher amount of FcεRI compared with those of −315C/C. The findings demonstrate that a −315 SNP significantly affects human FcεRI α-chain promoter activity and expression level of FcεRI on basophils by binding different transcription factors to the SNP site.
Immunotherapy with CpG Oligonucleotides and Antibodies to TNF-α Rescues Neonatal Mice from Lethal Arenavirus-Induced Meningoencephalitis
Authors: Pedras-Vasconcelos João A. , Puig Montserrat , Sauder Christian , Wolbert Candie , Ovanesov Mikhail , Goucher David , Verthelyi Daniela 
Published: April 2014

Abstract
Viral encephalitides are life-threatening diseases in neonates partly due to the irreversible damage inflammation causes to the CNS. This study explored the role of proinflammatory cytokines in the balance between controlling viral replication and eliciting pathologic immune responses in nonlytic viral encephalitis. We show that neonatal mice challenged with arenavirus Tacaribe (TCRV) develop a meningoencephalitis characterized by high IFN-γ and TNF-α levels and mild T cell infiltration. Neutralization of the TNF-α using mAb was associated with lower chemokine expression, reduced T cell infiltration, and lower levels of IFN-γ, and TNF-α in the CNS and led to 100% survival. Moreover, treatment with Abs to TNF-α improved mobility and increased survival even after the mice developed bilateral hind limb paralysis. Of note, animals treated with anti-TNF-α Abs alone did not clear the virus despite generating Abs to TCRV. Direct activation of the innate immune response using CpG oligodeoxynucleotides in combination with anti-TNF-α Abs resulted in 100% survival and complete viral clearance. To our knowledge, this is the first demonstration of the use of innate immune modulators plus Abs to TNF-α as therapeutics for a lethal neurotropic viral infection.
Francisella Targets Cholesterol-Rich Host Cell Membrane Domains for Entry into Macrophages
Authors: Tamilselvam Batcha , Daefler Simon 
Published: April 2014

Abstract
Francisella tularensis is a pathogen optimally adapted to efficiently invade its respective host cell and to proliferate intracellularly. We investigated the role of host cell membrane microdomains in the entry of F. tularensis subspecies holarctica vaccine strain (F. tularensis live vaccine strain) into murine macrophages. F. tularensis live vaccine strain recruits cholesterol-rich lipid domains (“lipid rafts”) with caveolin-1 for successful entry into macrophages. Interference with lipid rafts through the depletion of plasma membrane cholesterol, through induction of raft internalization with choleratoxin, or through removal of raft-associated GPI-anchored proteins by treatment with phosphatidylinositol phospholipase C significantly inhibited entry of Francisella and its intracellular proliferation. Lipid raft-associated components such as cholesterol and caveolin-1 were incorporated into Francisella-containing vesicles during entry and the initial phase of intracellular trafficking inside the host cell. These findings demonstrate that Francisella requires cholesterol-rich membrane domains for entry into and proliferation inside macrophages.
E1A Oncogene Enhancement of Caspase-2-Mediated Mitochondrial Injury Sensitizes Cells to Macrophage Nitric Oxide-Induced Apoptosis
Authors: Radke Jay R. , Siddiqui Zeba K. , Miura Tanya A. , Routes John M. , Cook James L. 
Published: April 2014

Abstract
The adenovirus E1A oncogene induces innate immune rejection of tumors by sensitizing tumor cells to apoptosis in response to injuries, such as those inflicted by macrophage-produced TNF α and NO. E1A sensitizes cells to TNF by repressing its activation of NF-κB-dependent, antiapoptotic defenses. This suggested the hypothesis that E1A blockade of the NF-κB activation response might be the central mechanism of E1A induced cellular sensitivity to other proapoptotic injuries, such as macrophage-produced NO. However, creation of E1A-positive NIH-3T3 mouse cell variants with high-level, NF-κB-dependent resistance to TNF did not coselect for resistance to apoptosis induced by either macrophage-NO or chemical-NO, as the hypothesis would predict. E1A expression did block cellular recovery from NO-induced mitochondrial injury and converted the reversible, NO-induced cytostasis response of cells to an apoptotic response. This viral oncogene-induced phenotypic conversion of the cellular injury response of mouse and human cells was mediated by an E1A-related increase in NO-induced activation of caspase-2, an apical initiator of intrinsic apoptosis. Blocking caspase-2 activation or expression eliminated the NO-induced apoptotic response of E1A-positive cells. These results define an NF-κB-independent pathway through which the E1A gene of human adenovirus sensitizes mouse and human cells to apoptosis by enhancement of caspase-2-mediated mitochondrial injury.
Flagellin Treatment Protects against Chemicals, Bacteria, Viruses, and Radiation
Authors: Vijay-Kumar Matam , Aitken Jesse D. , Sanders Catherine J. , Frias Amena , Sloane Valerie M. , Xu Jianguo , Neish Andrew S. , Rojas Mauricio , Gewirtz Andrew T. 
Published: April 2014

Abstract
Sudden exposure of human populations to chemicals, pathogens, or radiation has the potential to result in substantial morbidity. A potential means of rapidly protecting such populations might be to activate innate host defense pathways, which can provide broad protection against a variety of insults. However, innate immune activators can, by themselves, result in severe inflammatory pathology, which in large part is driven by hemopoietic-derived cytokines such as TNF-α. We reasoned that, because it preferentially activates epithelial cells, the TLR5 agonist flagellin might not induce severe inflammatory pathology and yet be an ideal agent to provide such non-specific protection, particularly at the mucosal surfaces that serve as a front line of host defense. In accordance, we observed that systemic treatment of mice with purified flagellin did not induce the serologic, histopathologic, and clinical hallmarks of inflammation that are induced by LPS but yet protected mice against chemicals, pathogens, and ionizing radiation. Flagellin-elicited radioprotection required TLR5, the TLR signaling adaptor MyD88, and was effective if given between 2 h before to 4 h after exposure to irradiation. Flagellin-elicited radioprotection was, in part, mediated via effects on cells in bone marrow but yet rescued mortality without a pronounced rescue of radiation-induced anemia or leukopenia. Thus, systemic administration of flagellin may be a relatively safe means of providing temporary non-specific protection against a variety of challenges.
Lutzomyia longipalpisSalivary Peptide Maxadilan Alters Murine Dendritic Cell Expression of CD80/86, CCR7, and Cytokine Secretion and Reprograms Dendritic Cell-Mediated Cytokine Release from Cultures Containing Allogeneic T Cells
Authors: Wheat William H. , Pauken Kristen E. , Morris Robin V. , Titus Richard G. 
Published: April 2014

AbstractLeishmania protozoan parasites, the etiologic agent of leishmaniasis, are transmitted exclusively by phlebotomine sand flies of the genera Phlebotomus and Lutzomyia. In addition to parasites, the infectious bite inoculum contains arthropod salivary components. One well-characterized salivary component from Lutzomyia longipalpis is maxadilan (MAX), a vasodilator acting via the type I receptor for the pituitary cyclic AMP activating peptide. MAX has been shown to elicit immunomodulatory effects potentially dictating immune responses to Leishmania parasites. When exposed to MAX, both resting and LPS-stimulated dendritic cells (DCs) show reduced CD80 and CD86 expression on most DCs in vitro. However, CD86 expression is increased significantly on a subpopulation of DCs. Furthermore, MAX treatment promoted secretion of type 2 cytokines (IL-6 and IL-10) while reducing production of type 1 cytokines (IL-12p40, TNF-α, and IFN-γ) by LPS-stimulated DCs. A similar trend was observed in cultures of MAX-treated DCs containing naive allogeneic CD4+ T cells: type 2 cytokines (IL-6 and IL-13) increased while type 1 cytokines (TNF-α and IFN-γ) decreased. Additionally, the proinflammatory cytokine IL-1β was increased in cultures containing MAX-treated mature DCs. MAX treatment of LPS-stimulated DCs also prevented optimal surface expression of CCR7 in vitro. These MAX-dependent effects were evident in DCs from both Leishmania major-susceptible (BALB/c) and -resistant (C3H/HeN) murine strains. These data suggest that modification of DC phenotype and function by MAX likely affects crucial cellular components that determine the pathological response to infection with Leishmania.
The Central Memory CD4+ T Cell Population Generated duringLeishmania majorInfection Requires IL-12 to Produce IFN-γ
Authors: Pakpour Nazzy , Zaph Colby , Scott Phillip 
Published: April 2014

AbstractCentral memory CD4+ T cells provide a pool of lymph node-homing, Ag-experienced cells that are capable of responding rapidly after a secondary infection. We have previously described a population of central memory CD4+ T cells in Leishmania major-infected mice that were capable of mediating immunity to a secondary infection. In this study, we show that the Leishmania-specific central memory CD4+ T cells require IL-12 to produce IFN-γ, demonstrating that this population needs additional signals to develop into Th1 cells. In contrast, effector cells isolated from immune mice produced IFN-γ in vitro or in vivo in the absence of IL-12. In addition, we found that when central memory CD4+ T cells were adoptively transferred into IL-12-deficient hosts, many of the cells became IL-4 producers. These studies indicate that the central memory CD4+ T cell population generated during L. major infection is capable of developing into either Th1 or Th2 effectors. Thus, continued IL-12 production may be required to ensure the development of Th1 cells from this central memory T cell pool, a finding that has direct relevance to the design of vaccines dependent upon central memory CD4+ T cells.
Role of Chicken TL1A on Inflammatory Responses and Partial Characterization of Its Receptor
Authors: Takimoto Tetsuya , Sato Kan , Akiba Yukio , Takahashi Kazuaki 
Published: April 2014

AbstractThe role of chicken TNF-like ligand 1A (ChTL1A) on inflammation and its receptor candidates was investigated to further understand its function as a proinflammatory cytokine. ChTL1A decreased the viability of CHO-K1 cells transfected with chicken TNFR2 or decoy receptor 3 and bound to TNFR2 and decoy receptor 3. ChTL1A was detected in chicken blood samples taken 4 h after LPS injection. Increased mRNA for inflammatory response-related factors such as IL-1β, IL-6, ChTL1A, IFN-γ, inducible NO synthase, and cyclooxygenase 2 were found in spleen samples following LPS injection. Ceruloplasmin and α1 acid glycoprotein (as positive acute phase proteins) were increased in chicken plasma 12 h after ChTL1A injection. The injection of anti-ChTL1A Ab was able to prevent typical increases in plasma nitrite plus nitrate, ceruloplasmin, and α1 acid glycoprotein concentrations following LPS injection. These results indicate that ChTL1A is a proinflammatory cytokine in chickens, animals that do not have TNF-α and lymphotoxin α orthologous genes, and that its proinflammatory action is, at least in part, expressed through binding to TNFR2.
CCL11 and GM-CSF Differentially Use the Rho GTPase Pathway to Regulate Motility of Human Eosinophils in a Three-Dimensional Microenvironment
Authors: Muessel Michelle J. , Scott Karen S. , Friedl Peter , Bradding Peter , Wardlaw Andrew J. 
Published: April 2014

Abstract
Asthma is a common disease that causes considerable morbidity. Increased numbers of airway eosinophils are a hallmark of asthma. Mechanisms controlling the entry of eosinophils into asthmatic lung have been intensively investigated, but factors regulating migration within the tissue microenvironment are less well understood. We modeled this by studying chemoattractant and growth factor-mediated human eosinophil migration within a three-dimensional collagen matrix. Stimulation with GM-CSF induced dose-dependent, random migration with a maximum of 77 ± 4.7% of cells migrating. In contrast, CCL11 and C5a caused a more modest although significant degree of migration (19 ± 1.8% and 20 ± 2.6%, respectively). Migration to GM-CSF was partially dependent on Ca2+ and αΜβ2 integrins. The Rho family of small GTPases regulates intracellular signaling of cell migration. GM-CSF-induced migration was only partially dependent on Rho kinase/Rho-associated kinase (ROCK) and was independent of RhoA activation. In contrast, CCL11-induced migration was fully dependent on both RhoA and ROCK. Activation of RhoA was therefore neither necessary nor sufficient to cause eosinophil migration in a three-dimensional collagen environment. This study suggests that eosinophil growth factors are likely to be required for eosinophil migration within the bronchial mucosa, and this involves signal transduction pathways distinct from those used by G protein-associated chemoattractants.
Defective Generation of a Humoral Immune Response Is Associated with a Reduced Incidence and Severity of Collagen-Induced Arthritis in Microsomal Prostaglandin E Synthase-1 Null Mice
Authors: Kojima Fumiaki , Kapoor Mohit , Yang Lihua , Fleishaker Erica L. , Ward Martin R. , Monrad Seetha U. , Kottangada Ponnappa C. , Pace Charles Q. , Clark James A. , Woodward Jerold G. , Crofford Leslie J. 
Published: April 2014

Abstract
Microsomal PGE synthase-1 (mPGES-1) is an inducible enzyme that acts downstream of cyclooxygenase and specifically catalyzes the conversion of PGH2 to PGE2. The present study demonstrates the effect of genetic deletion of mPGES-1 on the developing immunologic responses and its impact on the clinical model of bovine collagen-induced arthritis. mPGES-1 null and heterozygous mice exhibited decreased incidence and severity of arthritis compared with wild-type mice in a gene dose-dependent manner. Histopathological examination revealed significant reduction in lining hyperplasia and tissue destruction in mPGES-1 null mice compared with their wild-type littermates. mPGES-1 deficient mice also exhibited attenuation of mechanical nociception in a gene dose-dependent manner. In addition, mPGES-1 null and heterozygous mice showed a marked reduction of serum IgG against type II collagen, including subclasses IgG1, IgG2a, IgG2b, IgG2c, and IgG3, compared with wild-type mice, which correlated with the reduction in observed inflammatory features. These results demonstrate for the first time that deficiency of mPGES-1 inhibits the development of collagen-induced arthritis, at least in part, by blocking the development of a humoral immune response against type II collagen. Pharmacologic inhibition of mPGES-1 may therefore impact both the inflammation and the autoimmunity associated with human diseases such as rheumatoid arthritis.