bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proinflammatory Chemokines, Such as C-C Chemokine Ligand 3, Desensitize μ-Opioid Receptors on Dorsal Root Ganglia Neurons
Authors: Zhang Ning , Rogers Thomas J. , Caterina Michael , Oppenheim Joost J. 
Published: April 2014

Abstract
Pain is one of the hallmarks of inflammation. Opioid receptors mediate antipain responses in both the peripheral nervous system and CNS. In the present study, pretreatment of CCR1:μ-opioid receptor/HEK293 cells with CCL3 (MIP-1α) induced internalization of μ-opioid receptors and severely impaired the μ-opioid receptor-mediated inhibition of cAMP accumulation. Immunohistochemical staining showed that CCR1 and μ-opioid receptors were coexpressed on small to medium diameter neurons in rat dorsal root ganglion. Analysis of ligand-induced calcium flux showed that both types of receptors were functional. Pretreatment of neurons with CCL3 exhibited an impaired [d-Ala2,N-MePhe4,Gly-o15]enkephalin-elicited calcium response, indicative of the heterologous desensitization of μ-opioid receptors. Other chemokines, such as CCL2, CCL5, and CXCL8, exhibited similar inhibitory effects. Our data indicate that proinflammatory chemokines are capable of desensitizing μ-opioid receptors on peripheral sensory neurons, providing a novel potential mechanism for peripheral inflammation-induced hyperalgesia.
Evidence That Invasion-Inhibitory Antibodies Specific for the 19-kDa Fragment of Merozoite Surface Protein-1 (MSP-119) Can Play a Protective Role against Blood-Stage Plasmodium falciparum Infection in Individuals in a Malaria Endemic Area of Africa
Authors: John Chandy C. , O’Donnell Rebecca A. , Sumba Peter O. , Moormann Ann M. , de Koning-Ward Tania F. , King Christopher L. , Kazura James W. , Crabb Brendan S. 
Published: April 2014

Abstract
The C-terminal 19-kDa fragment of Plasmodium falciparum merozoite surface protein-1 (MSP-119) is a target of protective Abs against blood-stage infection and a leading candidate for inclusion in a human malaria vaccine. However, the precise role, relative importance, and mechanism of action of Abs that target this protein remain unclear. To examine the potential protective role of Abs to MSP-119 in individuals naturally exposed to malaria, we conducted a treatment time to infection study over a 10-wk period in 76 residents of a highland area of western Kenya during a malaria epidemic. These semi-immune individuals were not all equally susceptible to reinfection with P. falciparum following drug cure. Using a new neutralization assay based on transgenic P. falciparum expressing the P. chabaudi MSP-119 orthologue, individuals with high-level MSP-119-specific invasion-inhibitory Abs (&gt;75th percentile) had a 66% reduction in the risk of blood-stage infection relative to others in the population (95% confidence interval, 3–88%). In contrast, high levels of MSP-119 IgG or IgG subclass Abs measured by enzyme immunoassay with six different recombinant MSP-119 Ags did not correlate with protection from infection. IgG Abs measured by serology and functional invasion-inhibitory activity did not correlate with each other. These findings implicate an important protective role for MSP-119-specific invasion inhibitory Abs in immunity to blood-stage P. falciparum infection, and suggest that the measurement of MSP-119 specific inhibitory Abs may serve as an accurate correlate of protection in clinical trials of MSP-1-based vaccines.
Rac2-Deficient Murine Macrophages Have Selective Defects in Superoxide Production and Phagocytosis of Opsonized Particles
Authors: Yamauchi Akira , Kim Chaekyun , Li Shijun , Marchal Christophe C. , Towe Jason , Atkinson Simon J. , Dinauer Mary C. 
Published: April 2014

Abstract
The Rho family GTPase Rac is a crucial participant in numerous cellular functions and acts as a molecular switch for signal transduction. Mice deficient in hemopoietic-specific Rac2 exhibited agonist-specific defects in neutrophil functions including chemoattractant-stimulated filamentous actin polymerization and chemotaxis, and superoxide production elicited by phorbol ester, fMLP, or IgG-coated particles, despite expression of the highly homologous Rac1 isoform. In this study, functional responses of Rac2-null murine macrophages were characterized to examine whether Rac2 also has nonredundant functions in this phagocytic lineage. In contrast to murine neutrophils, in which Rac1 and Rac2 are present in similar amounts, Rac1 was ∼4-fold more abundant than Rac2 in both bone marrow-derived and peritoneal exudate macrophages, and macrophage Rac1 levels were unchanged by the absence of Rac2. Accumulation of exudate macrophages during peritoneal inflammation was reduced in rac2−/− mice. FcγR-mediated phagocytosis of IgG-coated SRBC was also significantly decreased in Rac2-null macrophages, as was NADPH oxidase activity in response to phorbol ester or FcγR stimulation. However, phagocytosis and oxidant production stimulated by serum-opsonized zymosan was normal in rac2−/− macrophages. Macrophage morphology was also similar in wild-type and Rac2-null cells, as was actin polymerization induced by FcγR-mediated phagocytosis or M-CSF. Hence, Rac2-null macrophages have selective defects paralleling many of the observed functional defects in Rac2-null neutrophils. These results provide genetic evidence that although Rac2 is a relatively minor isoform in murine macrophages, it plays a nonoverlapping role with Rac1 to regulate host defense functions in this phagocyte lineage.
Regulated Recruitment of MHC Class II and Costimulatory Molecules to Lipid Rafts in Dendritic Cells
Authors: Meyer zum Bueschenfelde Christian O. , Unternaehrer Julia , Mellman Ira , Bottomly Kim 
Published: April 2014

Abstract
T cell activation has long been associated with the partitioning of Ag receptors and associated molecules to lipid microdomains. We now show that dendritic cells (DCs) also accomplish the selective recruitment to lipid rafts of molecules critical for Ag presentation. Using mouse bone marrow-derived DCs, we demonstrate that MHC class II molecules become substantially localized to rafts upon DC maturation. Even more striking is the fact that CD86 is recruited to rafts upon T cell-DC interaction. Recruitment is Ag dependent and requires CD28 on T cells. Despite the regulated recruitment of MHC class II and CD86 to rafts, unlike the counter-receptors in T cells, DCs do not polarize these molecules to sites of DC-T cell contact. This difference may reflect the necessity for DCs to interact with multiple T cells simultaneously and emphasizes that the biochemical and morphological correlates of lipid rafts are not necessarily equivalent.
The Class A Macrophage Scavenger Receptor Attenuates CXC Chemokine Production and the Early Infiltration of Neutrophils in Sterile Peritonitis
Authors: Cotena Alessia , Gordon Siamon , Platt Nick 
Published: April 2014

Abstract
The macrophage scavenger receptor (SR-A) is a multifunctional receptor that is associated with several important pathological conditions, including atherosclerosis. In this study, we show, using a sterile peritonitis model, that it can regulate the inflammatory response. SR-A null mice display an increased initial granulocytic infiltration because of overproduction of the CXC chemokines, MIP-2 and keratinocyte-derived cytokine. This differential response is dependent upon particle internalization and can be mimicked by advanced glycation end product-BSA-conjugated latex beads. Thus SR-A is a nonactivating receptor, which is the first example of a pattern recognition receptor that serves to counter the activities of proinflammatory receptors and attenuates the production of specific chemokines to ensure an inflammatory response of the appropriate magnitude.
Group IB Secretory Phospholipase A2 Stimulates CXC Chemokine Ligand 8 Production via ERK and NF-κB in Human Neutrophils
Authors: Jo Eun Jin , Lee Ha-Young , Lee Youl-Nam , Kim Jung Im , Kang Hyun-Kyu , Park Dae-Won , Baek Suk-Hwan , Kwak Jong-Young , Bae Yoe-Sik 
Published: April 2014

Abstract
Although the level of group IB secretory phospholipase A2 (sPLA2-IB) has been reported to be up-regulated during inflammatory response, the role of sPLA2-IB on the regulation of inflammation and immune responses has not been fully elucidated. In this study, we found that sPLA2-IB stimulates the expression and secretion of CXCL8 without affecting other proinflammatory cytokines, such as IL-1β or TNF α in human neutrophils. The induction of CXCL8 secretion by sPLA2-IB occurs at both the transcription and translational levels and correlates with activation of NF-κB. Moreover, the NF-κB inhibitors pyrrolidinedithiocarbamate, dexamethasone, or sulfasalazine were found to prevent CXCL8 production by sPLA2-IB in human neutrophils. In addition, the signaling events induced by sPLA2-IB included activation of the MAPK ERK and an increase in intracellular Ca2+, which are both required for CXCL8 production. The exogenous addition of sPLA2-IB did not induce arachidonic acid release from human neutrophils, and the inactivation of sPLA2-IB by EGTA did not affect CXCL8 production by sPLA2-IB in human neutrophils. Taken together, we suggest that sPLA2-IB plays a role in the modulation of inflammatory and immune responses via the sPLA2 receptor, by inducing CXCL8 in human neutrophils.
Differential Regulation of Th2 and Th1 Lung Inflammatory Responses by Protein Kinase Cθ
Authors: Salek-Ardakani Shahram , So Takanori , Halteman Beth S. , Altman Amnon , Croft Michael 
Published: April 2014

Abstract
In vitro and recent in vivo studies have identified protein kinase Cθ (PKCθ) as an important intermediate in signaling pathways leading to T cell activation, proliferation, and cytokine production. However, the importance of PKCθ to many T cell-driven inflammatory responses has not been demonstrated. In this study we show that although PKCθ is required for the development of a robust lung inflammatory response controlled by Th2 cells, it plays a lesser role in the development of a similar lung inflammatory response controlled by Th1 cells. PKCθ-deficient mice were strongly compromised in generating Th2 cells and exhibited reduced airway eosinophilia and Th2 cytokine production in lungs. PKCθ was required for the initial development of Th1 cells, with these cells exhibiting delayed kinetics of differentiation and accumulation. However, with recall Ag challenge via the airways, this defect was overcome, and lung infiltration and Th1 cytokine production were largely unimpaired in PKCθ-deficient animals. These data suggest that PKCθ can play roles in aspects of both Th2 and Th1 responses, but lung inflammation induced by Th2 cells is more dependent on this protein kinase than lung inflammation induced by Th1 cells.
Suppression of Ongoing Experimental Autoimmune Encephalomyelitis by Neutralizing the Function of the p28 Subunit of IL-27
Authors: Goldberg Ruth , Zohar Yaniv , Wildbaum Gizi , Geron Yifat , Maor Gila , Karin Nathan 
Published: April 2014

Abstract
IL-27 is a recently defined family member of the long-chain, four-helix bundle cytokines, which consist of EBI3, an IL-12p40-related protein, and p28, an IL-12p35-related polypeptide. The role of IL-27 in the regulation of experimental autoimmune encephalomyelitis has never been studied. We show in this study that neutralizing the in vivo function of IL-27 by Abs against IL-27 p28 rapidly suppressed an ongoing long-lasting disease in C57BL/6 mice. These Abs were then used to determine the mechanistic basis of disease suppression. We show in this study that IL-27 is involved not only in the polarization of naive T cells undergoing Ag-specific T cell activation, but also in promoting the proliferation and IFN-γ production by polarized T cells, including the long term Th1 line that has been previously selected against the target encephalitogenic determinant. This may explain in part why neutralizing IL-27 suppresses an already established disease in a very rapid and significant manner.
Cutting Edge: IL-5 Primes Th2 Cytokine-Producing Capacity in Eosinophils through a STAT5-Dependent Mechanism
Authors: Zhu Yuechun , Chen Luqiu , Huang Zan , Alkan Serhan , Bunting Kevin D. , Wen Renren , Wang Demin , Huang Hua 
Published: April 2014

Abstract
Both type-2 CD4+ Th cells (CD4+Th2) and type-2 innate effector cells play critical roles in generating type-2 immunity that can either be protective against parasitic infection or cause tissue damage in allergy and asthma. How innate effector cells acquire the capacity to produce Th2 cytokines is not entirely known. We previously showed that IL-4 induced differentiation of Th2 cytokine-producing eosinophils. To determine whether other Th2 cytokines can also induce Th2 cytokine-producing capacity in innate effector cells, we cultured bone marrow progenitor cells in the presence of various Th2 cytokines. IL-5, but not IL-13 or IL-25, primed bone marrow progenitor cells to differentiate into robust IL-4-producing cells. The majority of IL-4-producing cells induced by IL-5 were eosinophils. Importantly, IL-5 completely depended on STAT5 to promote IL-4-producing capacity in eosinophils. Thus, our study demonstrates that IL-5 functions as a potent factor that drives bone marrow progenitor cells into IL-4-producing eosinophils.
Cutting Edge: Critical Role for CD5 in Experimental Autoimmune Encephalomyelitis: Inhibition of Engagement Reverses Disease in Mice
Authors: Axtell Robert C. , Webb Matthew S. , Barnum Scott R. , Raman Chander 
Published: April 2014

AbstractThe induction phase of experimental autoimmune encephalomyelitis (EAE) in mice is T cell dependent and coreceptors that regulate T cell activation modulate disease development. We report here that mice lacking CD5, an important modulator of T cell activation, exhibit significantly delayed onset and decreased severity of EAE. The resistance to EAE in CD5−/− mice was not due to the inability of T cells to respond efficiently to stimulation with MOG35–55 but was associated with the presence of elevated frequency of apoptotic activated T cells in spleens and DLN. We also observed a net decrease in peripheral activated CD4+ T cells in CD5−/− spleens and DLN 10 days after immunization. We further show that in vivo blockade of CD5 engagement after induction of EAE by soluble CD5-Fc, a treatment that induces elimination of activated T cells, promoted recovery from EAE. Our studies indicate that CD5 regulates survival of activated T cells and provides a target for treatment of T cell-dependent autoimmune diseases such as multiple sclerosis.
CD4+CD25+ Cells Controlling a Pathogenic CD4 Response Inhibit Cytokine Differentiation, CXCR-3 Expression, and Tissue Invasion
Authors: Sarween Nadia , Chodos Anna , Raykundalia Chandra , Khan Mahmood , Abbas Abul K. , Walker Lucy S. K. 
Published: April 2014

AbstractIt is well established that CD4+CD25+ regulatory T cells (Tregs) inhibit autoimmune pathology. However, precisely how the behavior of disease-inducing T cells is altered by Tregs remains unclear. In this study we use a TCR transgenic model of diabetes to pinpoint how pathogenic CD4 T cells are modified by Tregs in vivo. We show that although Tregs only modestly inhibit CD4 cell expansion, they potently suppress tissue infiltration. This is associated with a failure of CD4 cells to differentiate into effector cells and to up-regulate the IFN-γ-dependent chemokine receptor CXCR-3, which confers the ability to respond to pancreatic islet-derived CXCL10. Our data support a model in which Tregs permit T cell activation, yet prohibit T cell differentiation and migration into Ag-bearing tissues.
Lymphocyte Development and Function in the Absence of Retinoic Acid-Related Orphan Receptor α
Authors: Dzhagalov Ivan , Giguère Vincent , He You-Wen 
Published: April 2014

Abstract
The orphan nuclear receptor, retinoid acid-related orphan receptor (ROR)α, is essential for the development of cerebellar Purkinje cells and bone tissue. RORα may also play a critical role in lymphocyte development and function because staggerer mice, a natural mutant strain with a disrupted expression of RORα, have reduced thymic and splenic cellularity. In this report, we analyzed the role of RORα in lymphocyte development by examining lymphoid compartments in RORα−/− mice and Rag-2−/− mice reconstituted with RORα−/− bone marrow. We found that T and B cell development was severely defective in RORα−/− mice, but not in Rag-2−/−/RORα−/− chimeric mice. We also analyzed cellular and humoral immune responses in Rag-2−/−/RORα−/− chimeric mice. Our results show that serum IgG levels were elevated in Rag-2−/−/RORα−/− chimeric mice after immunization with a T-dependent Ag compared with control chimeras. IFN-γ production by RORα−/− CD8+ T cells after TCR stimulation was also increased. Furthermore, RORα−/− mast cells and macrophages produced an increased amount of TNF-α and IL-6 upon activation. These results indicate that RORα indirectly regulates lymphocyte development by providing an appropriate microenvironment and controls immune responses by negatively regulating cytokine production in innate immune cells and lymphocytes.
Lipid Rafts Mediate Association of LFA-1 and CD3 and Formation of the Immunological Synapse of CTL
Authors: Marwali Muhammad Reza , MacLeod Matthew A. , Muzia David N. , Takei Fumio 
Published: April 2014

AbstractLipid rafts accumulate in the immunological synapse formed by an organized assembly of the TCR/CD3, LFA-1, and signaling molecules. However, the precise role of lipid rafts in the formation of the immunological synapse is unclear. In this study, we show that LFA-1 on CTL is constitutively active and mediates Ag-independent binding of CTL to target cells expressing its ligands. LFA-1 and CD3 on CTL, but not resting T cells, colocalize in lipid rafts. Binding of LFA-1 on CTL to targets initiates the formation of the immunological synapse, which is formed by LFA-1, CD3, and ganglioside GM1 distributed in the periphery of the cell contact site and cholesterol is more widely distributed. The formation of this synapse is Ag independent, but the recognition of Ag by the TCR induces accumulation of tyrosine phosphorylated proteins in the synapse as well as redistribution of the microtubule organization center toward the cell contact site. Our results suggest that LFA-1 recruits lipid rafts and the TCR/CD3 to the synapse, and facilitates efficient and rapid activation of CTL.
Caspase-8 Serves Both Apoptotic and Nonapoptotic Roles
Authors: Kang Tae-Bong , Ben-Moshe Tehila , Varfolomeev Eugene E. , Pewzner-Jung Yael , Yogev Nir , Jurewicz Anna , Waisman Ari , Brenner Ori , Haffner Rebecca , Gustafsson Erika , Ramakrishnan Parameswaran , Lapidot Tsvee , Wallach David 
Published: April 2014

AbstractKnockout of caspase-8, a cysteine protease that participates in the signaling for cell death by receptors of the TNF/nerve growth factor family, is lethal to mice in utero. To explore tissue-specific roles of this enzyme, we established its conditional knockout using the Cre/loxP recombination system. Consistent with its role in cell death induction, deletion of caspase-8 in hepatocytes protected them from Fas-induced caspase activation and death. However, application of the conditional knockout approach to investigate the cause of death of caspase-8 knockout embryos revealed that this enzyme also serves cellular functions that are nonapoptotic. Its deletion in endothelial cells resulted in degeneration of the yolk sac vasculature and embryonal death due to circulatory failure. Caspase-8 deletion in bone-marrow cells resulted in arrest of hemopoietic progenitor functioning, and in cells of the myelomonocytic lineage, its deletion led to arrest of differentiation into macrophages and to cell death. Thus, besides participating in cell death induction by receptors of the TNF/nerve growth factor family, caspase-8, apparently independently of these receptors, also mediates nonapoptotic and perhaps even antiapoptotic activities.
Phosphatidylserine Regulates the Maturation of Human Dendritic Cells
Authors: Chen Xiao , Doffek Kara , Sugg Sonia L. , Shilyansky Joel 
Published: April 2014

Abstract
Phosphatidylserine (PS), which is exposed on the surface of apoptotic cells, has been implicated in immune regulation. However, the effects of PS on the maturation and function of dendritic cells (DCs), which play a central role in both immune activation and regulation, have not been described. Large unilamellar liposomes containing PS or phosphatidylcholine were used to model the plasma membrane phospholipid composition of apoptotic and live cells, respectively. PS liposomes inhibited the up-regulation of HLA-ABC, HLA-DR, CD80, CD86, CD40, and CD83, as well as the production of IL-12p70 by human DCs in response to LPS. PS did not affect DC viability directly but predisposed DCs to apoptosis in response to LPS. DCs exposed to PS had diminished capacity to stimulate allogeneic T cell proliferation and to activate IFN-γ-producing CD4+ T cells. Exogenous IL-12 restored IFN-γ production by CD4+ T cells. Furthermore, activated CTLs proliferated poorly to cognate Ag presented by DCs exposed to PS. Our findings suggest that PS exposure provides a sufficient signal to inhibit DC maturation and to modulate adaptive immune responses.
Bcl-2 Transduction Protects Human Endothelial Cell Synthetic Microvessel Grafts from Allogeneic T Cells In Vivo
Authors: Zheng Lian , Gibson Thomas F. , Schechner Jeffrey S. , Pober Jordan S. , Bothwell Alfred L. M. 
Published: April 2014

AbstractT cell interactions with vascular endothelial cells (EC) are of central importance for immune surveillance of microbes and for pathological processes such as atherosclerosis, allograft rejection, and vasculitis. Animal (especially rodent) models incompletely predict human immune responses, in particular with regard to the immunological functions of EC, and in vitro models may not accurately reflect in vivo findings. In this study, we describe the development of an immunodeficient SCID/bg murine model combining a transplanted human synthetic microvascular bed with adoptive transfer of human T lymphocytes allogeneic to the cells of the graft that more fully recapitulates T cell responses in natural tissues. Using this model, we demonstrate that transduced Bcl-2 protein in the engrafted EC effectively prevents injury even as it enhances T cell graft infiltration and replication.
Characterization of the Systemic Loss of Dendritic Cells in Murine Lymph Nodes During Polymicrobial Sepsis
Authors: Efron Philip A. , Martins Antonio , Minnich Douglas , Tinsley Kevin , Ungaro Ricardo , Bahjat Frances R. , Hotchkiss Richard , Clare-Salzler Michael , Moldawer Lyle L. 
Published: April 2014

Abstract
Dendritic cells (DCs) play a key role in critical illness and are depleted in spleens from septic patients and mice. To date, few studies have characterized the systemic effect of sepsis on DC populations in lymphoid tissues. We analyzed the phenotype of DCs and Th cells present in the local (mesenteric) and distant (inguinal and popliteal) lymph nodes of mice with induced polymicrobial sepsis (cecal ligation and puncture). Flow cytometry and immunohistochemical staining demonstrated that there was a significant local (mesenteric nodes) and partial systemic (inguinal, but not popliteal nodes) loss of DCs from lymph nodes in septic mice, and that this process was associated with increased apoptosis. This sepsis-induced loss of DCs occurred after CD3+CD4+ T cell activation and loss in the lymph nodes, and the loss of DCs was not preceded by any sustained increase in their maturation status. In addition, there was no preferential loss of either mature/activated (MHCIIhigh/CD86high) or immature (MHCIIlow/CD86low) DCs during sepsis. However, there was a preferential loss of CD8+ DCs in the local and distant lymph nodes. The loss of DCs in lymphoid tissue, particularly CD8+ lymphoid-derived DCs, may contribute to the alterations in acquired immune status that frequently accompany sepsis.