bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recombinant CD200 Protein Does Not Bind Activating Proteins Closely Related to CD200 Receptor
Authors: Hatherley Deborah , Cherwinski Holly M. , Moshref Mehrdad , Barclay A. Neil 
Published: April 2014

Abstract
CD200 (OX2) is a cell surface glycoprotein that interacts with a structurally related receptor (CD200R) expressed mainly on myeloid cells and is involved in regulation of macrophage and mast cell function. In mouse there are up to five genes related to CD200R with conflicting data as to whether they bind CD200. We show that mouse CD200 binds the inhibitory receptor CD200R with a comparable affinity (Kd = 4 μM) to those found for the rat and human CD200 CD200R interactions. CD200 gave negligible binding to the activating receptors, CD200RLa, CD200RLb, and CD200RLc, by direct analysis at the protein level using recombinant monomeric and dimeric fusion proteins or to CD200RLa and CD200RLb when expressed at the cell surface. An additional potential activating gene, CD200RLe, found in only some mouse strains also did not bind CD200. Thus, the CD200 receptor family consists of both activatory and inhibitory members like several other paired ligand receptors, such as signal regulatory protein, killer cell Ig-like receptor/KAR, LY49, dendritic cell immunoreceptor/dendritic cell immunoactivating receptor, and paired Ig-like type 2 receptor. Although the ligand for the inhibitory product is a widely distributed host protein, the ligands of the activating forms remain to be identified, and one possibility is that they are pathogen components.
Two Major Interacting Chromosome Loci Control Disease Susceptibility in Murine Model of Spondyloarthropathy
Authors: Végvári Anikó , Szabó Zoltán , Szántó Sándor , Nesterovitch Andrew B. , Mikecz Katalin , Glant Tibor T. , Adarichev Vyacheslav A. 
Published: April 2014

Abstract
Autoimmune spondylitis was induced in BALB/c mice and their MHC-matched (BALB/c × DBA/2)F1 and F2 hybrids by systemic immunization with cartilage/intervertebral disk proteoglycan (PG). As in human ankylosing spondylitis, the MHC was the major permissive genetic locus in murine PG-induced spondylitis (PGIS). Two major non-MHC chromosome loci with highly significant linkage were found on chromosomes 2 (Pgis2) and 18 (Pgis1) accounting for 40% of the entire F2 trait variance. The dominant spondylitis-susceptibility allele for Pgis2 locus is derived from the BALB/c strain, whereas the Pgis1 recessive allele was present in the disease-resistant DBA/2 strain. The Pgis1 locus significantly affected the disease-controlling Pgis2 locus, inducing as high incidence of spondylitis in F2 hybrids as was found in the spondylitis-susceptible parent BALB/c strain. Additional disease-controlling loci with suggestive linkage were mapped to the chromosomes 12, 15, and 19. Severity of spondylitis in F2 mice positively correlated with serum levels of amyloid A, IL-6, and Pg-specific Abs, and showed negative correlation with Ag-induced T cell proliferation, IFN-γ, IL-4, and TNF-α production. A major locus controlling serum IL-6 was found on chromosome 14 near osteoclast differentiation factor Tnfsf11. Locus on chromosome 11 near the Stat3 and Stat5 genes controlled serum level of the Ig IgG2a isotype. The two major genetic loci Pgis1 and Pgis2 of murine spondylitis were homologous to chromosome regions in human genome, which control ankylosing spondylitis in human patients. Thus, this animal model of experimentally induced spondylitis might facilitate the identification of spondylitis-susceptibility genes in humans.
Identification and Bioactivities of IFN-γ in Rainbow Trout Oncorhynchus mykiss: The First Th1-Type Cytokine Characterized Functionally in Fish
Authors: Zou Jun , Carrington Allison , Collet Bertrand , Dijkstra Johannes Martinus , Yoshiura Yasutoshi , Bols Niels , Secombes Chris 
Published: April 2014

Abstract
IFN-γ is one of the key cytokines in defining Th1 immune responses. In this study, an IFN-γ homologue has been identified in rainbow trout Oncorhynchus mykiss, and its biological activities have been characterized. The trout IFN-γ cDNA is 1034 bp in length and translates into a 180-aa protein. The first intron of the trout IFN-γ gene contains highly polymorphic GACA minisatellites and 44-bp DNA repeats, giving rise to at least six alleles. IFN-γ is structurally conserved among vertebrates, and a signature motif has been identified. A nuclear localization sequence known to be crucial for IFN-γ biological activities is also present in the C-terminal region of the trout IFN-γ. The IFN-γ expression was induced in head kidney leukocytes by stimulation with PHA or poly(I:C) and in kidney and spleen of fish injected with poly(I:C). rIFN-γ produced in Escherichia coli significantly stimulated gene expression of IFN-γ-inducible protein 10 (γIP-10), MHC class II β-chain, and STAT1, and enhanced respiratory burst activity in macrophages. Deletion of 29-aa residues from the C terminus containing the nuclear localization sequence motif resulted in loss of activity with respect to induction of γIP-10 in RTS-11 cells. Moreover, IFN-γ-induced γIP-10 expression was completely abolished by the protein kinase C inhibitor staurosporine, and partially reduced by U0126, a specific inhibitor for ERKs. Taken together, the present study has demonstrated for the first time a functional IFN-γ homologue in a fish species, strongly suggesting a conserved Th1 immune response is most likely present in lower vertebrates.
Plasmodium yoelii Can Ablate Vaccine-Induced Long-Term Protection in Mice
Authors: Wykes Michelle N. , Zhou Yong-Hong , Liu Xue Q. , Good Michael F. 
Published: April 2014

Abstract
Malaria is a serious cause of morbidity and mortality for people living in endemic areas, but unlike many other infections, individuals exposed to the parasite do not rapidly become resistant to subsequent infections. High titers of Ab against the 19-kDa C-terminal fragment of the merozoite surface protein-1 can mediate complete protection in model systems; however, previous studies had not determined whether this vaccine generated long-term protection. In this study, we report that functional memory cells generated by merozoite surface protein-1, per se, do not offer any protection. This is because the parasite induces deletion of vaccine-specific memory B cells as well as long-lived plasma cells including those specific for bystander immune responses. Our study demonstrates a novel mechanism by which Plasmodium ablates immunological memory of vaccines, which would leave the host immuno-compromised.
A Soluble Factor Secreted by an HIV-1-Resistant Cell Line Blocks Transcription through Inactivating the DNA-Binding Capacity of the NF-κB p65/p50 Dimer
Authors: Lesner Adam , Li Yuchang , Nitkiewicz Jadwiga , Li Guanhua , Kartvelishvili Alex , Kartvelishvili Magdalena , Simm Malgorzata 
Published: April 2014

Abstract
The identity and activity of several anti-HIV soluble factor(s) secreted by CD8 and CD4 T lymphocytes have been determined; however, some of them still await definition. We have established an HIV-1-resistant, transformed CD4 T cell line that secretes HIV-1 resistance protein(s). Our studies indicate that this protein(s), called HIV-1 resistance factor (HRF), inhibits transcription of the virus by interfering with the activity of NF-κB. In the present report we identified the site at which HRF exerts this inhibition by evaluating a set of discrete events in NF-κB action. We tested the κB oligonucleotide binding activity in nuclei of resistant cells, nuclear translocation and binding to the HIV-1 long terminal repeat of p65 and p50 proteins from susceptible cells after exposure to HRF, and the binding of recombinant p50 to the κB oligonucleotide in vitro as affected by prior or simultaneous exposure to HRF. The results of this experimental schema indicate that HRF interacts with p50 after it enters the nucleus, but before its binding to DNA and that this interaction impedes the formation of an NF-κB-DNA complex required for the promotion of transcription. These findings suggest that HRF mediates a novel innate immune response to virus infection.
Protease-Activated Receptor-2 Activation Induces Acute Lung Inflammation by Neuropeptide-Dependent Mechanisms
Authors: Su Xiao , Camerer Eric , Hamilton Justin R. , Coughlin Shaun R. , Matthay Michael A. 
Published: April 2014

Abstract
Protease-activated receptors (PARs) and tachykinin-immunoreactive fibers are located in the lung as sentries to respond to a variety of pathological stimuli. The effects of PAR activation on the lung have not been adequately studied. We report on the effects of instilling PAR-activating peptides (PAR-APs, including PAR1-, PAR2-, and PAR4-AP) into the lungs of ventilated or spontaneously breathing mice. PAR2-AP, but not PAR1-AP or PAR4-AP, caused a sharp increase in lung endothelial and epithelial permeability to protein, extravascular lung water, and airway tone. No responses to PAR2-AP were detected in PAR2 knockout mice. In bronchoalveolar lavage, PAR2 activation caused 8- and 5-fold increase in MIP-2 and substance P levels, respectively, and a 12-fold increase in the number of neutrophils. Ablation of sensory neurons (by capsaicin) markedly decreased the PAR2-mediated airway constriction, and virtually abolished PAR2-mediated pulmonary inflammation and edema, as did blockade of NK1 or NK2 receptors. Thus, PAR2 activation in the lung induces airway constriction, lung inflammation, and protein-rich pulmonary edema. These effects were either partly or completely neuropeptide dependent, suggesting that PAR2 can cause lung inflammation by a neurogenic mechanism.
IL-Converting Enzyme/Caspase-1 Inhibitor VX-765 Blocks the Hypersensitive Response to an Inflammatory Stimulus in Monocytes from Familial Cold Autoinflammatory Syndrome Patients
Authors: Stack Jeffrey H. , Beaumont Kevin , Larsen Paul D. , Straley Kimberly S. , Henkel Greg W. , Randle John C. R. , Hoffman Hal M. 
Published: April 2014

Abstract
Familial cold autoinflammatory syndrome (FCAS) and the related autoinflammatory disorders, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, are characterized by mutations in the CIAS1 gene that encodes cryopyrin, an adaptor protein involved in activation of IL-converting enzyme/caspase-1. Mutations in cryopyrin are hypothesized to result in abnormal secretion of caspase-1-dependent proinflammatory cytokines, IL-1β and IL-18. In this study, we examined cytokine secretion in PBMCs from FCAS patients and found a marked hyperresponsiveness of both IL-1β and IL-18 secretion to LPS stimulation, but no evidence of increased basal secretion of these cytokines, or alterations in basal or stimulated pro-IL-1β levels. VX-765, an orally active IL-converting enzyme/caspase-1 inhibitor, blocked IL-1β secretion with equal potency in LPS-stimulated cells from FCAS and control subjects. These results further link mutations in cryopyrin with abnormal caspase-1 activation, and support the clinical testing of caspase-1 inhibitors such as VX-765 in autoinflammatory disorders.
Cytokine Production by Skin-Derived Mast Cells: Endogenous Proteases Are Responsible for Degradation of Cytokines
Authors: Zhao Wei , Oskeritzian Carole A. , Pozez Andrea L. , Schwartz Lawrence B. 
Published: April 2014

AbstractThe current study characterizes the cytokine protein (ELISA) and mRNA (gene array and RT-PCR) profiles of skin-derived mast cells cultured under serum-free conditions when activated by cross-linking of FcεRI. Prior to mast cell activation, mRNA only for TNF-α was detected, while after activation mRNA for IL-5, IL-6, IL-13, TNF-α, and GM-CSF substantially increased, and for IL-4 it minimally increased. However, at the protein level certain recombinant cytokines, as measured by ELISAs, were degraded by proteases released by these skin-derived mast cells. IL-6 and IL-13 were most susceptible, followed by IL-5 and TNF-α; GM-CSF was completely resistant. These observations also held for the endogenous cytokines produced by activated mast cells. By using protease inhibitors, chymase and cathepsin G, not tryptase, were identified in the mast cell releasates as the likely culprits that digest these cytokines. Their cytokine-degrading capabilities were confirmed with purified chymase and cathepsin G. Soy bean trypsin inhibitor, when added to mast cell releasates, prevented the degradation of exogenously added cytokines and, when added to mast cells prior to their activation, prevented degradation of susceptible endogenous cytokines without affecting either degranulation or GM-CSF production. Consequently, substantial levels of IL-5, IL-6, IL-13, TNF-α, and GM-CSF were detected 24–48 h after mast cells had been activated, while none were detected 15 min after activation, by which time preformed granule mediators had been released. IL-4 was not detected at any time point. Thus, unless cytokines are protected from degradation by endogenous proteases, cytokine production by human mast cells with chymase and cathepsin G cells may be grossly underestimated.
Mechanisms of Peripheral Tolerance following Intracameral Inoculation Are Independent of IL-13 or STAT6
Authors: Nakamura Takahiko , Terajewicz Ania , Stein-Streilein Joan 
Published: April 2014

Abstract
The peripheral tolerance that is elicited by the anterior chamber-associated immune deviation (ACAID) protocol is characterized by impairment of Th1 responses such as delayed-type hypersensitivity. It has been proposed that suppression of Th1 responses is mediated by a deviation toward Th2 responses. Because NKT cells have a prominent role in ACAID and NKT cell-derived IL-13 is required in a tumor model of tolerance, we postulated that NKT cell-derived Th2 cytokines might have a role in ACAID. However, contrary to the tumor model, in this study we show that NKT cells from IL-13-deficient mice or IL-4/IL-13 double deficient mice were able to reconstitute the capability of Jα18-deficient mice (lacking invariant NKT) to develop peripheral tolerance postintracameral inoculation of Ag. Also, we were able to induce peripheral tolerance directly in IL-13-deficient, IL-4/IL-13-double deficient, and STAT6-deficient mice by inoculation of Ag into their eye. We conclude that neither IL-4 nor IL-13 cytokines are required for the generation of efferent CD8+ T regulatory cells during eye-induced peripheral tolerance. We propose that Ags inoculated into the anterior chamber of the eye induce the immunoresponse to deviate from producing immune T effector cells to producing efferent T regulatory cells, rather than deviating from Th1- to Th2-type effector cells.
CCR3 Expression and Function in Asthmatic Airway Smooth Muscle Cells
Authors: Joubert Philippe , Lajoie-Kadoch Stéphane , Labonté Isabelle , Gounni Abdelilah Soussi , Maghni Karim , Wellemans Vincent , Chakir Jamila , Laviolette Michel , Hamid Qutayba , Lamkhioued Bouchaib 
Published: April 2014

AbstractAsthma is characterized by an increase in airway smooth muscle mass and a decreased distance between the smooth muscle layer and the epithelium. Furthermore, there is evidence to indicate that airway smooth muscle cells (ASMC) express a wide variety of receptors involved in the immune response. The aims of this study were to examine the expression of CCR3 on ASMC, to compare this expression between asthmatic and nonasthmatic subjects, and to determine the implications of CCR3 expression in the migration of ASMC. We first demonstrated that ASMC constitutively express CCR3 at both mRNA and protein levels. Interestingly, TNF-α increases ASMC surface expression of CCR3 from 33 to 74%. Furthermore, using FACS analysis, we found that ASMC CCR3 is expressed to a greater degree in asthmatic vs control subjects (95 vs 75%). Functionality of the receptor was demonstrated by calcium assay; the addition of CCR3 ligand eotaxin to ASMC resulted in an increase in intracellular calcium production. Interestingly, ASMC was seen to demonstrate a positive chemotactic response to eotaxin. Indeed, ASMC significantly migrated toward 100 ng/ml eotaxin (2.2-fold increase, compared with control). In conclusion, the expression of CCR3 by ASMC is increased in asthmatics, and our data show that a CCR3 ligand such as eotaxin induces migration of ASMC in vitro. These results may suggest that eotaxin could be involved in the increased smooth muscle mass observed in asthmatics through the activation of CCR3.
Delivery of Dendritic Cells Engineered to Secrete IFN-α into Central Nervous System Tumors Enhances the Efficacy of Peripheral Tumor Cell Vaccines: Dependence on Apoptotic Pathways
Authors: Kuwashima Naruo , Nishimura Fumihiko , Eguchi Junichi , Sato Hidemitsu , Hatano Manabu , Tsugawa Takahiko , Sakaida Tsukasa , Dusak Jill E. , Fellows-Mayle Wendy K. , Papworth Glenn D. , Watkins Simon C. , Gambotto Andrea , Pollack Ian F. , Storkus Walter J. , Okada Hideho 
Published: April 2014

AbstractWe tested whether modulation of the CNS-tumor microenvironment by delivery of IFN-α-transduced dendritic cells (DCs: DC-IFN-α) would enhance the therapeutic efficacy of peripheral vaccinations with cytokine-gene transduced tumor cells. Mice bearing intracranial GL261 glioma or MCA205 sarcoma received peripheral immunizations with corresponding irradiated tumor cells engineered to express IL-4 or GM-CSFs, respectively, as well as intratumoral delivery of DC-IFN-α. This regimen prolonged survival of the animals and induced tumor-specific CTLs that expressed TRAIL, which in concert with perforin and Fas ligand (FasL) was involved in the tumor-specific CTL activity of these cells. The in vivo antitumor activity associated with this approach was abrogated by administration of neutralizing mAbs against TRAIL or FasL and was not observed in perforin−/−, IFN-γ−/−, or FasL−/− mice. Transduction of the tumor cells with antiapoptotic protein cellular FLIP rendered the gene-modified cells resistant to TRAIL- or FasL-mediated apoptosis and to CTL killing activity in vitro. Furthermore, the combination therapeutic regimen was ineffective in an intracranial cellular FLIP-transduced MCA205 brain tumor model. These results suggest that the combination of intratumoral delivery of DC-IFN-α and peripheral immunization with cytokine-gene transduced tumor cells may be an effective therapy for brain tumors that are sensitive to apoptotic signaling pathways.
Directing Transition from Innate to Acquired Immunity: Defining a Role for IL-6
Authors: Jones Simon A. 
Published: April 2014

Abstract
Appropriate control of leukocyte recruitment and activation is a fundamental requirement for competent host defense and resolving inflammation. A pivotal event that defines the successful outcome of any inflammatory event is the transition from innate to acquired immunity. In IL-6 deficiency, this process appears defective, and a series of in vivo studies have documented important roles for IL-6 in both the resolution of innate immunity and the development of acquired immune responses. Within this review, particular attention will be given to the regulatory properties of the soluble IL-6 receptor and how its activity may affect chronic disease progression.
Cutting Edge: Innate Immunity Conferred by B Cells Is Regulated by Caspase-8
Authors: Beisner Daniel R. , Ch’en Irene L. , Kolla Ravi V. , Hoffmann Alexander , Hedrick Stephen M. 
Published: April 2014

Abstract
Caspase-8 is an essential component of death receptor-mediated apoptosis. Along with Fas-associated death domain protein, it is also essential for T cell proliferation in response to antigenic or mitogenic stimuli. To determine whether caspase-8 is also required for B cell proliferation, we generated mice with a B cell-specific Casp8 deficiency. Unlike T cells, caspase-8 was not required for Ag receptor-driven proliferation or Ab formation. Rather, Casp8-deficient B cells failed to proliferate in response to dsRNA and LPS, ligands for TLR3 and TLR4, respectively, but responded normally to the TLR9 agonist CpG DNA. Similarly, Ab production to trinitrophenol-LPS was selectively reduced in B cell-specific Casp8-deficient mice. The activation of NF-κB or IFN regulatory factor 3 was found to be unaffected by the loss of caspase-8, implicating it in a novel pathway important for some forms of innate immunity mediated by B cells.
Neutrophils Lacking Platelet-Endothelial Cell Adhesion Molecule-1 Exhibit Loss of Directionality and Motility in CXCR2-Mediated Chemotaxis
Authors: Wu Yue , Stabach Paul , Michaud Michael , Madri Joseph A. 
Published: April 2014

Abstract
Time-lapsed videomicroscopy was used to study the migration of platelet-endothelial cell adhesion molecule-1-deficient (PECAM-1−/−) murine neutrophils undergoing chemotaxis in Zigmond chambers containing IL-8, KC, or fMLP gradients. PECAM-1−/− neutrophils failed to translocate up the IL-8, KC, and fMLP gradients. Significant reductions in cell motility and cell spreading were also observed in IL-8 or KC gradients. In wild-type neutrophils, PECAM-1 and F-actin were colocalized at the leading fronts of polarized cells toward the gradient. In contrast, in PECAM-1−/− neutrophils, although F-actin also localized to the leading front of migrating cells, F-actin polymerization was unstable, and cycling was remarkably increased compared with that of wild-type neutrophils. This may be due to the decreased cytokine-induced mobilization of the actin-binding protein, moesin, into the cytoskeleton of PECAM-1−/− neutrophils. PECAM-1−/− neutrophils also exhibited intracellularly dislocalized Src homology 2 domain containing phosphatase 1 (SHP-1) and had less IL-8-induced SHP-1 phosphatase activity. These results suggest that PECAM-1 regulates neutrophil chemotaxis by modulating cell motility and directionality, in part through its effects on SHP-1 localization and activation.
Transgenic Expression of Helios in B Lineage Cells Alters B Cell Properties and Promotes Lymphomagenesis
Authors: Dovat Sinisa , Montecino-Rodriguez Encarnacion , Schuman Valerie , Teitell Michael A. , Dorshkind Kenneth , Smale Stephen T. 
Published: April 2014

Abstract
Helios, a member of the Ikaros family of DNA-binding proteins, is expressed in multipotential lymphoid progenitors and throughout the T lineage. However, in most B lineage cells, Helios is not expressed, suggesting that its absence may be critical for B cell development and function. To test this possibility, transgenic mice were generated that express Helios under the control of an Ig μ enhancer. Commitment to the B cell lineage was unaltered in Helios transgenic mice, and numbers of surface IgM+ B cells were normal in the bone marrow and spleen. However, both bone marrow and splenic B cells exhibited prolonged survival and enhanced proliferation. B cells in Helios transgenic mice were also hyperresponsive to Ag stimulation. These alterations were observed even though the concentration of ectopic Helios in B lineage cells, like that of endogenous Helios in thymocytes, was well below the concentration of Ikaros. Further evidence that ectopic Helios expression contributes to B cell abnormalities was provided by the observation that Helios transgenic mice developed metastatic lymphoma as they aged. Taken together, these results demonstrate that silencing of Helios is critical for normal B cell function.