bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monocyte Migration and LFA-1-Mediated Attachment to Brain Microvascular Endothelia Is Regulated by SDF-1α through Lyn Kinase
Authors: Malik Mobeen , Chen Ying-Yu , Kienzle Martha F. , Tomkowicz Brian E. , Collman Ronald G. , Ptasznik Andrzej 
Published: April 2014

Abstract
Infiltration of activated monocytes into the brain is a prerequisite for the development of various neurological disorders such as HIV-associated dementia, multiple sclerosis, and other inflammatory processes. In these pathologies, the chemokine SDF-1α (CXCL12) is over-expressed and might attract monocytes into the CNS. We demonstrate here that SDF-1α stimulates migration of monocytes through its receptor, CXCR4, and decreases monocyte adherence to surfaces coated with ICAM-1, a ligand for β2 integrins. SDF-1α also decreases monocyte adherence to brain microvascular endothelial cells (BMVEC) that are activated with TNF-α, IL-1β, or recombinant envelope glycoprotein from HIV-1, which increase BMVEC expression of ICAM-1. The decreased adherence is linked to down-regulation on monocytes of the activation-dependent epitope of the β2 integrin LFA-1 by SDF-1α. Knockdown of Lyn in monocytes using small interfering RNA decreases SDF-1α-mediated migration and prevents the inhibition of monocyte attachment to ICAM-1 and activated BMVEC. Thus, in SDF-1α-stimulated monocytes, Lyn acts as a positive regulator of migration and a negative regulator of adhesion to BMVEC through the LFA-1 integrin. These results provide a novel Lyn-mediated signaling mechanism for the regulation of monocyte movement at the blood-brain barrier.
Type I IFNs Play a Role in Early Resistance, but Subsequent Susceptibility, to the African Trypanosomes
Authors: Lopez Rebecca , Demick Karen P. , Mansfield John M. , Paulnock Donna M. 
Published: April 2014

Abstract
Macrophages express a spectrum of proinflammatory and regulatory mediators during African trypanosomiasis. Microarray analyses revealed similar profiles of induced genes in macrophages stimulated with the trypanosome soluble variant surface glycoprotein in vitro and in macrophages taken from infected mice. Genes associated with the acute phase response and with type I IFN responses were prominent components of the macrophage activation profiles expressed within 72 h in vitro and in vivo. Thus, induction of proinflammatory gene expression is a characteristic of early trypanosome infection that is driven primarily by soluble variant surface glycoprotein exposure, and it may be that IFN-α/β plays a central role in regulation of early resistance to trypanosomes. To test this hypothesis, we assessed parameters of infection in mouse strains with genetic alterations in the IFN-α/β response pathway. We found that Ifnar1−/− mice, which lack the receptor for type I IFNs, exhibited delayed control of parasite burden during the first week of infection and died earlier than did wild-type controls. However, infection of Ubp43−/− mice, which are hyperresponsive to type I IFNs, did not exhibit enhanced resistance to trypanosomes. Instead, these animals also failed to control parasite burden and were more susceptible than wild-type animals. Additionally, the Ubp43−/− mice exhibited a significant defect in IFN-γ production, which is definitively linked to host resistance in trypanosomiasis. These results show that type I IFNs play a role in early control of parasites in infected mice but may contribute to down-regulation of IFN-γ production and subsequent loss of host resistance later in infection.
Cathelicidin Administration Protects Mice from Bacillus anthracis Spore Challenge
Authors: Lisanby Mark W. , Swiecki Melissa K. , Dizon Brian L. P. , Pflughoeft Kathryn J. , Koehler Theresa M. , Kearney John F. 
Published: April 2014

Abstract
Cathelicidins are a family of cationic peptides expressed in mammals that possess numerous bactericidal and immunomodulatory properties. In vitro analyses showed that human, mouse, and pig cathelicidins inhibited Bacillus anthracis bacterial growth at micromolar concentrations in the presence or absence of capsule. Combined in vitro analyses of the effects of each peptide on spore germination and vegetative outgrowth by time lapse phase contrast microscopy, transmission electron microscopy, and flow cytometric analysis showed that only the pig cathelicidin was capable of directly arresting vegetative outgrowth and killing the developing bacilli within the confines of the exosporium. C57BL/6 mice were protected from spore-induced death by each cathelicidin in a time- and dose-dependent manner. Protection afforded by the porcine cathelicidin was due to its bactericidal effects, whereas the human and mouse cathelicidins appeared to mediate protection through increased recruitment of neutrophils to the site of infection. These findings suggest that cathelicidins might be utilized to augment the initial innate immune response to B. anthracis spore exposure and prevent the development of anthrax.
Annexin A1 Regulates Intestinal Mucosal Injury, Inflammation, and Repair
Authors: Babbin Brian A. , Laukoetter Mike G. , Nava Porfirio , Koch Stefan , Lee Winston Y. , Capaldo Christopher T. , Peatman Eric , Severson Eric A. , Flower Roderick J. , Perretti Mauro , Parkos Charles A. , Nusrat Asma 
Published: April 2014

Abstract
During mucosal inflammation, a complex array of proinflammatory and protective mechanisms regulates inflammation and severity of injury. Secretion of anti-inflammatory mediators is a mechanism that is critical in controlling inflammatory responses and promoting epithelial restitution and barrier recovery. AnxA1 is a potent anti-inflammatory protein that has been implicated to play a critical immune regulatory role in models of inflammation. Although AnxA1 has been shown to be secreted in intestinal mucosal tissues during inflammation, its potential role in modulating the injury/inflammatory response is not understood. In this study, we demonstrate that AnxA1-deficient animals exhibit increased susceptibility to dextran sulfate sodium (DSS)-induced colitis with greater clinical morbidity and histopathologic mucosal injury. Furthermore, impaired recovery following withdrawal of DSS administration was observed in AnxA1 (−/−) animals compared with wild-type (WT) control mice that was independent of inflammatory cell infiltration. Since AnxA1 exerts its anti-inflammatory properties through stimulation of ALX/FPRL-1, we explored the role of this receptor-ligand interaction in regulating DSS-induced colitis. Interestingly, treatment with an ALX/FPRL-1 agonist, 15-epi-lipoxin A4 reversed the enhanced sensitivity of AnxA1 (−/−) mice to DSS colitis. In contrast, 15-epi-lipoxin A4 did not significantly improve the severity of disease in WT animals. Additionally, differential expression of ALX/FPLR-1 in control and DSS-treated WT and AnxA1-deficient animals suggested a potential role for AnxA1 in regulating ALX/FPRL-1 expression under pathophysiological conditions. Together, these results support a role of endogenous AnxA1 in the protective and reparative properties of the intestinal mucosal epithelium.
STAT4 Isoforms Differentially Regulate Th1 Cytokine Production and the Severity of Inflammatory Bowel Disease
Authors: O'Malley John T. , Eri Rajaraman D. , Stritesky Gretta L. , Mathur Anubhav N. , Chang Hua-Chen , HogenEsch Harm , Srinivasan Mythily , Kaplan Mark H. 
Published: April 2014

Abstract
STAT4, a critical regulator of inflammation in vivo, can be expressed as two alternative splice forms, a full-length STAT4α, and a STAT4β isoform lacking a C-terminal transactivation domain. Each isoform is sufficient to program Th1 development through both common and distinct subsets of target genes. However, the ability of these isoforms to mediate inflammation in vivo has not been examined. Using a model of colitis that develops following transfer of CD4+ CD45RBhigh T cells expressing either the STAT4α or STAT4β isoform into SCID mice, we determined that although both isoforms mediate inflammation and weight loss, STAT4β promotes greater colonic inflammation and tissue destruction. This correlates with STAT4 isoform-dependent expression of TNF-α and GM-CSF in vitro and in vivo, but not Th1 expression of IFN-γ or Th17 expression of IL-17, which were similar in STAT4α- and STAT4β-expressing T cells. Thus, higher expression of a subset of inflammatory cytokines from STAT4β-expressing T cells correlates with the ability of STAT4β-expressing T cells to mediate more severe inflammatory disease.
Stimulatory Role of Lysophosphatidic Acid in Cyclooxygenase-2 Induction by Synovial Fluid of Patients with Rheumatoid Arthritis in Fibroblast-Like Synovial Cells
Authors: Nochi Hiromi , Tomura Hideaki , Tobo Masayuki , Tanaka Nobuyuki , Sato Koichi , Shinozaki Tetsuya , Kobayashi Tsutomu , Takagishi Kenji , Ohta Hideo , Okajima Fumikazu , Tamoto Koichi 
Published: April 2014

Abstract
While inflammatory cytokines are well-recognized critical factors for the induction of cyclooxygenase-2 (COX-2) in activated fibroblast-like synovial cells, the roles of biologically active components other than inflammatory cytokines in synovial fluid remain unknown. Herein, we assessed the role of lysophosphatidic acid (LPA), a pleiotropic lipid mediator, in COX-2 induction using synovial fluid of patients with rheumatoid arthritis (RA) in fibroblast-like RA synovial cells. Synovial fluid from RA patients stimulated COX-2 induction, which was associated with prostaglandin E2 production, in RA synovial cells. The synovial fluid-induced actions were inhibited by Gi/o protein inhibitor pertussis toxin and LPA receptor antagonist 3-(4-[4-([1-(2-chlorophenyl)ethoxy]carbonyl amino)-3-methyl-5-isoxazolyl] benzylsulfanyl) propanoic acid (Ki16425). In fact, LPA alone significantly induced COX-2 expression and enhanced IL-1α- or IL-1β-induced enzyme expression in a manner sensitive to pertussis toxin and Ki16425. RA synovial cells abundantly expressed LPA1 receptor compared with other LPA receptor subtypes. Moreover, synovial fluid contains a significant amount of LPA, an LPA-synthesizing enzyme autotaxin, and its substrate lysophosphatidylcholine. In conclusion, LPA existing in synovial fluid plays a critical role in COX-2 induction in collaboration with inflammatory cytokines in RA synovial cells. Ki16425-sensitive LPA receptors may be therapeutic targets for RA.
Requirements for Effective Antitumor Responses of TCR Transduced T Cells
Authors: de Witte Moniek A. , Jorritsma Annelies , Kaiser Andrew , van den Boom Marly D. , Dokter Maarten , Bendle Gavin M. , Haanen John B. A. G. , Schumacher Ton N. M. 
Published: April 2014

Abstract
Adoptive transfer of TCR gene-modified T cells has been proposed as an attractive approach to target tumors for which it is difficult or impossible to induce strong tumor-specific T cell responses by vaccination. Whereas the feasibility of generating tumor Ag-specific T cells by gene transfer has been demonstrated, the factors that determine the in vivo effectiveness of TCR-modified T cells are largely unknown. We have analyzed the value of a number of clinically feasible strategies to enhance the antitumor potential of TCR modified T cells. These experiments reveal three factors that contribute greatly to the in vivo potency of TCR-modified T cells. First, irradiation-induced host conditioning is superior to vaccine-induced activation of genetically modified T cells. Second, increasing TCR expression through genetic optimization of TCR sequences has a profound effect on in vivo antitumor activity. Third, a high precursor frequency of TCR modified T cells within the graft is essential. Tumors that ultimately progress in animals treated with this optimized regimen for TCR-based adoptive cell transfer invariably display a reduced expression of the target Ag. This suggests TCR gene therapy can achieve a sufficiently strong selective pressure to warrant the simultaneous targeting of multiple Ags. The strategies outlined in this study should be of value to enhance the antitumor activity of TCR-modified T cells in clinical trials.
Gene Expression Profiling in Autoimmune Noninfectious Uveitis Disease
Authors: Li Zhuqing , Liu Baoying , Maminishkis Arvydas , Mahesh Sankaranarayana P. , Yeh Steven , Lew Julie , Lim Wee Kiak , Sen H. Nida , Clarke Grace , Buggage Ronald , Miller Sheldon S. , Nussenblatt Robert B. 
Published: April 2014

AbstractNoninfectious uveitis is a predominantly T cell-mediated autoimmune, intraocular inflammatory disease. To characterize the gene expression profile from patients with noninfectious uveitis, PBMCs were isolated from 50 patients with clinically characterized noninfectious uveitis syndrome. A pathway-specific cDNA microarray was used for gene expression profiling and real-time PCR array for further confirmation. Sixty-seven inflammation- and autoimmune-associated genes were found differentially expressed in uveitis patients, with 28 of those genes being validated by real-time PCR. Several genes previously unknown for autoimmune uveitis, including IL-22, IL-19, IL-20, and IL-25/IL-17E, were found to be highly expressed among uveitis patients compared with the normal subjects with IL-22 expression highly variable among the patients. Furthermore, we show that IL-22 can affect primary human retinal pigment epithelial cells by decreasing total tissue resistance and inducing apoptosis possibly by decreasing phospho-Bad level. In addition, the microarray data identified a possible uveitis-associated gene expression pattern, showed distinct gene expression profiles in patients during periods of clinical activity and quiescence, and demonstrated similar expression patterns in related patients with similar clinical phenotypes. Our data provide the first evidence that a subset of IL-10 family genes are implicated in noninfectious uveitis and that IL-22 can affect human retinal pigment epithelial cells. The results may facilitate further understanding of the molecular mechanisms of autoimmune uveitis and other autoimmune originated inflammatory diseases.
Cutting Edge: TLR Ligands Increase TCR Triggering by Slowing Peptide-MHC Class I Decay Rates
Authors: Rudd Brian D. , Brien James D. , Davenport Miles P. , Nikolich-Žugich Janko 
Published: April 2014

Abstract
TLR ligands are among the key stimuli driving the optimal dendritic cell (DC) maturation critical for strong and efficacious T cell priming. In this study, we show that part of this effect occurs via increased TCR triggering. Pretreatment of DCs with TLR ligands resulted in the triggering of many more TCRs in responding CD8+ T cells. Importantly, even when DCs expressed the same amount of cognate peptide-MHC (pMHC) molecules, TLR ligand treatment resulted in down-regulation of larger numbers of TCR molecules. This was independent of the up-regulation of costimulatory, adhesion or cytokine molecules or the amount of noncognate pMHCs. Rather, DCs pretreated with TLR ligands exhibited increased stability of cognate pMHCs, enabling extended TCR triggering. These findings are of potential importance to T cell vaccination.
Cutting Edge: CD47 Controls the In Vivo Proliferation and Homeostasis of Peripheral CD4+CD25+Foxp3+ Regulatory T Cells That Express CD103
Authors: Van Vu Quang , Darwiche Jinane , Raymond Marianne , Lesage Sylvie , Bouguermouh Salim , Rubio Manuel , Sarfati Marika 
Published: April 2014

Abstract
Peripheral CD103+Foxp3+ regulatory T cells (Tregs) can develop both from conventional naive T cells upon cognate Ag delivery under tolerogenic conditions and from thymic-derived, expanded/differentiated natural Tregs. We here show that CD47 expression, a marker of self on hematopoietic cells, selectively regulated CD103+Foxp3+ Treg homeostasis at the steady state. First, the proportion of effector/memory-like (CD44highCD62Llow) CD103+Foxp3+ Tregs rapidly augmented with age in CD47-deficient mice (CD47−/−) as compared with age-matched control littermates. Yet, the percentage of quiescent (CD44lowCD62Lhigh) CD103−Foxp3+ Tregs remained stable. Second, the increased proliferation rate (BrdU incorporation) observed within the CD47−/−Foxp3+ Treg subpopulation was restricted to those Tregs expressing CD103. Third, CD47−/− Tregs maintained a normal suppressive function in vitro and in vivo and their increased proportion in old mice led to a decline of Ag-specific T cell responses. Thus, sustained CD47 expression throughout life is critical to avoid an excessive expansion of CD103+ Tregs that may overwhelmingly inhibit Ag-specific T cell responses.
Spontaneous Colitis Occurrence in Transgenic Mice with Altered B7-Mediated Costimulation
Authors: Kim Gisen , Turovskaya Olga , Levin Matthew , Byrne Fergus R. , Whoriskey John S. , McCabe James G. , Kronenberg Mitchell 
Published: April 2014

Abstract
The B7 costimulatory molecules govern many aspects of T cell immune responses by interacting with CD28 for costimulation, but also with CTLA-4 for immune suppression. Although blockade of CTLA-4 with Ab in humans undergoing cancer immune therapy has led to some cases of inflammatory bowel disease, spontaneous animal models of colitis that depend upon modulation of B7 interactions have not been previously described. In this study, we demonstrate that mice expressing a soluble B7-2 Ig Fc chimeric protein spontaneously develop colitis that is dependent on CD28-mediated costimulation of CD4+ T cells. We show that the chimeric protein has mixed agonistic/antagonist properties, and that it acts in part by blocking the cell intrinsic effects on T cell activation of engagement of CTLA-4. Disease occurred in transgenic mice that lack expression of the endogenous B7 molecules (B7 double knock-out mice), because of the relatively weak costimulatory delivered by the chimeric protein. Surprisingly, colitis was more severe in this context, which was associated with the decreased number of Foxp3+ regulatory T cells in transgenic B7 double knock-out mice. This model provides an important tool for examining how B7 molecules and their effects on CTLA-4 modulate T cell function and the development of inflammatory diseases.
The Exocytosis Regulator Synaptotagmin V Controls Phagocytosis in Macrophages
Authors: Vinet Adrien F. , Fukuda Mitsunori , Descoteaux Albert 
Published: April 2014

Abstract
Synaptotagmins (Syts) play a key role in the regulation of Ca2+-triggered exocytosis and membrane fusion events, two crucial events associated to the phagocytic process. In the present study, we investigated the role of Syt V, a regulator of focal exocytosis, in phagocytosis. In macrophages, Syt V is localized on recycling endosomes and on filopodia-like structures and is recruited to the nascent phagosomes independently of the phagocytic receptor engaged. Silencing of Syt V by RNA interference revealed a role for this protein for phagocytosis, particularly under conditions of high membrane demand. In contrast, silencing of Syt V had no effect on the recruitment of the lysosomal marker LAMP1 to phagosomes, indicating that phagosome maturation is not regulated by Syt V. Collectively, these results illustrate the importance of Syt V in the regulation of an important innate function of macrophages. Furthermore, our results are consistent with the concept that focal exocytosis of endocytic organelles is a key event in phagocytosis and suggest that Syt V regulates this process.
Casitas B-Lineage Lymphoma b Inhibits Antigen Recognition and Slows Cell Cycle Progression at Late Times during CD4+ T Cell Clonal Expansion
Authors: Zhang Ruan , Zhang Na , Mueller Daniel L. 
Published: April 2014

Abstract
Optimal clonal expansion of CD4+ T cells during the primary response to Ag requires prolonged TCR recognition of peptide Ag/MHC complexes. In this study, we investigated the capacity of Casitas B-lineage lymphoma b (Cbl-b) to counter-regulate late TCR signals necessary for continued cell division in vivo. During the first 24 h of a primary response to Ag, Cblb−/− 5C.C7 CD4+ T cells demonstrated no alteration in CD69, CD25, and CD71 up-regulation or cell growth as compared with wild-type cells. Nevertheless, beyond 24 h, both the expression of CD71 and the rate of cell division were increased in the genetic absence of Cbl-b, leading to an augmented clonal expansion. This deregulation of late T cell proliferation in the absence of Cbl-b resulted in part from an inability of Cblb−/− T cells to desensitize Akt, PLCγ-1, and ERK phosphorylation events downstream of the TCR/CD3 complex, in addition to their failure to undergo a growth arrest in the absence of Ag. These observations now suggest a novel role for Cbl-b in triggering the exit from cell cycle at the end of a CD4+ T cell clonal expansion.
Imidazoquinoline Acts as Immune Adjuvant for Functional Alteration of Thymic Stromal Lymphopoietin-Mediated Allergic T Cell Response
Authors: Torii Yoshitaro , Ito Tomoki , Amakawa Ryuichi , Sugimoto Hiroyuki , Amuro Hideki , Tanijiri Tsutomu , Katashiba Yuichi , Ogata Makoto , Yokoi Takashi , Fukuhara Shirou 
Published: April 2014

Abstract
Atopic dermatitis is a major allergic disease that develops through dysregulation of Th2-mediated inflammation. Although dendritic cells (DCs) have been thought to play a critical role in the upstream phase of the allergic cascade, conventional drugs such as steroids and chemical mediator antagonists target the effector cells or factors in allergic inflammation. Recently, it has been demonstrated that interaction between thymic stromal lymphopoietin (TSLP) and human DCs plays an essential role in evoking inflammatory Th2 responses in allergy through OX40 ligand expression on DCs. In this study, we provide evidence that R848, an imidazoquinoline compound, which is a TLR ligand and a strong Th1 response-inducing reagent, is a potent adjuvant for the alteration of the Th2-inducing potency of human DCs activated by TSLP (TSLP-DCs). R848 inhibited the inflammatory Th2-inducing capacity of TSLP-DCs and redirected them to possessing an IL-10 and IFN-γ-producing regulatory Th1-inducing capacity. This functional alteration depended on both repression of OX40 ligand expression and induction of IL-12 production from DCs by the addition of R848. Additionally, R848 had the ability to inhibit the TSLP-mediated expansion and maintenance of the Th2 memory response. These findings suggest that imidazoquinoline may be a useful in the treatment of allergic diseases that are triggered by TSLP.
Astrocytic Regulation of Human Monocytic/Microglial Activation
Authors: Kostianovsky Alex M. , Maier Lisa M. , Anderson Richard C. , Bruce Jeffrey N. , Anderson David E. 
Published: April 2014

Abstract
Recent reports have described reduced immunological responsiveness and stimulatory capacity among monocytes/microglia that infiltrate malignant human gliomas. Herein, we demonstrate that culture of ex vivo human monocytes or primary human microglia with tumor cells isolated from glioblastoma multiforme (GBM) specimens renders them tolerogenic, capable of suppressing the function of ex vivo monocytes in the absence of tumor cells or their soluble factors. We demonstrate that the tolerance induced in monocytes/microglia by GBM tumor cells is not associated with interference with the signaling cascade associated with TLR- or CD40-induced monocyte activation. Rather, these tumor cells appear to up-regulate pathways that antagonize positive signaling pathways, including but not limited to STAT3 and STAT5. Finally, we demonstrate that the tolerogenic properties of GBM tumor cells amplify properties inherent to nontransformed astrocytes. Future studies that identify all of the molecular mechanisms by which astrocytes and malignant gliomas suppress monocyte/microglial function will have dual therapeutic benefits: suppressing these pathways may benefit patients with astrocytic tumors, while enhancing them may benefit patients with autoimmune processes within the CNS, such as multiple sclerosis.