bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immature Dendritic Cells (DCs) Use Chemokines and Intercellular Adhesion Molecule (ICAM)-1, But Not DC-Specific ICAM-3-Grabbing Nonintegrin, to Stimulate CD4+ T Cells in the Absence of Exogenous Antigen
Authors: Real Eliana , Kaiser Andrew , Raposo Graça , Amara Ali , Nardin Alessandra , Trautmann Alain , Donnadieu Emmanuel 
Published: April 2014

Abstract
Dendritic cells (DCs) possess a number of unique features that distinguish them from other APCs. One such feature is their ability to trigger Ag-independent responses in T cells. Previous studies have focused on mature DCs, but the prevalence of this phenomenon in the resting-state immature DCs has never been considered. In this study, we show that, in the absence of Ag, human immature DCs trigger multiple responses in autologous primary CD4+ T cells, namely, increased motility, small Ca2+ transients, and up-regulation of CD69. These responses are particularly marked in CD4+ memory T cells. By using several experimental approaches, we found that DC-specific ICAM-3-grabbing nonintegrin plays no role in the induction of T cell responses, whereas ICAM-1/LFA-1 interactions are required. In addition, DC-produced chemokines contribute to the Ag-independent T cell stimulatory ability of DCs, because pertussis toxin-treated T cells exhibit diminished responses to immature DCs. More particularly, CCL17 and CCL22, which are constitutively produced by immature DCs, mediate both T cell polarization and attraction. Thus, immature DCs owe part of their outstanding Ag-independent T cell stimulatory ability to chemokines and ICAM-1, but not DC-specific ICAM-3-grabbing nonintegrin.
The Low Molecular Weight GTPase RhoA and Atypical Protein Kinase Cζ Are Required for TLR2-Mediated Gene Transcription
Authors: Teusch Nicole , Lombardo Eleuterio , Eddleston Jane , Knaus Ulla G. 
Published: April 2014

Abstract
The Rho GTPases are molecular switches that regulate many essential cellular processes, including actin dynamics, gene transcription, cell cycle progression, cell adhesion, and motility. In this study, we report that stimulation of TLR2 in human epithelial and monocytic cells leads to rapid and transient activation of RhoA. RhoA cooperated with the canonical I-κB kinase-mediated pathway that induces the release of NF-κB, in regulating the trans activation of the NF-κB subunit p65/RelA by affecting Ser311 phosphorylation, and subsequent cytokine production. Another consequence of TLR2 stimulation by bacterial derived products was the activation of atypical protein kinase C (PKC) ζ and association of this protein kinase with RhoA. Inhibition of PKCζ decreased NF-κB activation and p65/RelA trans activation without affecting I-κBα degradation. The observation of a transient, stimulus-dependent association of RhoA with PKCζ suggests that RhoA mediates at least partially its effect on gene transcription through atypical PKC. In contrast to previous studies, identifying Rac1-PI3K as an upstream element in TLR2-initiated response to NF-κB, PI3K signaling was not required for RhoA or PKCζ activity. These results indicate that multiple GTPase-regulated pathways emerge from stimulated Toll receptors, controlling different aspects of NF-κB-mediated gene transcription.
Activity of α- and θ-Defensins against Primary Isolates of HIV-1
Authors: Wang Wei , Owen Sherry M. , Rudolph Donna L. , Cole Alexander M. , Hong Teresa , Waring Alan J. , Lal Renu B. , Lehrer Robert I. 
Published: April 2014

Abstract
θ-Defensins are lectin-like, cyclic octadecapeptides found in the leukocytes of nonhuman primates. They are also homologues of the more familiar α-defensins expressed by humans and certain other mammals. This study compares the ability of six θ-defensins (hominid retrocyclins 1–3 and rhesus θ-defensins 1–3) and four human α-defensins (human neutrophil peptides (HNPs) 1–4) to bind gp120 and CD4. In addition, we compared the ability of these θ-defensins and HNP-1 to protect J53-BL cells (an indicator cell line) from primary HIV-1 isolates that varied in subtype and coreceptor usage. The most potent θ-defensin, retrocyclin-2, bound with exceptionally high affinity to gp120 (KD, 9.4 nM) and CD4 (KD, 6.87 nM), and its effectiveness against subtype B isolates (IC50, 1.05 ± 0.28 μg/ml; 520 ± 139 nM) was approximately twice as great as that of HNP-1 on a molar basis. We also show, for the first time, that human α-defensins, HNPs 1–3, are lectins that bind with relatively high affinity to gp120 (KD range, 15.8–52.8 nM) and CD4 (KD range, 8.0–34.9 nM). Proteins found in human and FBS bound exogenous HNP-2 and retrocyclin-1, and competed with their ability to bind gp120. However, even the low concentrations of α-defensins found in normal human serum suffice to bind over half of the gp120 spikes on HIV-1 and a higher percentage of cell surface CD4 molecules. Although this report principally concerns the relationship between carbohydrate-binding and the antiviral properties of α- and θ-defensins, the lectin-like behavior of defensins may contribute to many other activities of these multifunctional peptides.
High Bactericidal Efficiency of Type IIA Phospholipase A2 against Bacillus anthracis and Inhibition of Its Secretion by the Lethal Toxin
Authors: Gimenez Alejandro Piris , Wu Yong-Zheng , Paya Miguel , Delclaux Christophe , Touqui Lhousseine , Goossens Pierre L. 
Published: April 2014

Abstract
There is a considerable body of evidence supporting the role of secretory type II-A phospholipase A2 (sPLA2-IIA) as an effector of the innate immune response. This enzyme also exhibits bactericidal activity especially toward Gram-positive bacteria. In this study we examined the ability of sPLA2-IIA to kill Bacillus anthracis, the etiological agent of anthrax. Our results show that both germinated B. anthracis spores and encapsulated bacilli were sensitive to the bactericidal activity of recombinant sPLA2-IIA in vitro. In contrast, nongerminated spores were resistant. This bactericidal effect was correlated to the ability of sPLA2-IIA to hydrolyze bacterial membrane phospholipids. Guinea pig alveolar macrophages, the major source of sPLA2-IIA in an experimental model of acute lung injury, released enough sPLA2-IIA to kill extracellular B. anthracis. The production of sPLA2-IIA was significantly inhibited by B. anthracis lethal toxin. Human bronchoalveolar lavage fluids from acute respiratory distress syndrome patients are known to contain sPLA2-IIA; bactericidal activity against B. anthracis was detected in a high percentage of these samples. This anthracidal activity was correlated to the levels of sPLA2-IIA and was abolished by an sPLA2-IIA inhibitor. These results suggest that sPLA2-IIA may play a role in innate host defense against B. anthracis infection and that lethal toxin may help the bacteria to escape from the bactericidal action of sPLA2-IIA by inhibiting the production of this enzyme.
Double Mechanism for Apical Tryptophan Depletion in Polarized Human Bronchial Epithelium
Authors: Zegarra-Moran Olga , Folli Chiara , Manzari Benedetta , Ravazzolo Roberto , Varesio Luigi , Galietta Luis J. V. 
Published: April 2014

Abstract
Indoleamine 2,3-dioxygenase is an enzyme that catabolizes tryptophan to kynurenine. We investigated the consequences of IDO induction by IFN-γ in polarized human bronchial epithelium. IDO mRNA expression was undetectable in resting conditions, but strongly induced by IFN-γ. We determined the concentration of tryptophan and kynurenine in the extracellular medium, and we found that apical tryptophan concentration was lower than the basolateral in resting cells. IFN-γ caused a decrease in tryptophan concentration on both sides of the epithelium. Kynurenine was absent in control conditions, but increased in the basolateral medium after IFN-γ treatment. The asymmetric distribution of tryptophan and kynurenine suggested the presence of a transepithelial amino acid transport. Uptake experiments with radiolabeled amino acids demonstrated the presence of a Na+-dependent amino acid transporter with broad specificity that was responsible for the tryptophan/kynurenine transport. We confirmed these data by measuring the short-circuit currents elicited by direct application of tryptophan or kynurenine to the apical surface. The rate of amino acid transport was dependent on the transepithelial potential, and we established that in cystic fibrosis epithelia, in which the transepithelial potential is significantly more negative than in noncystic fibrosis epithelia, amino acid uptake was reduced. This work suggests that human airway epithelial cells maintain low apical tryptophan concentrations by two mechanisms, a removal through a Na+-dependent amino acid transporter and an IFN-γ-inducible degradation by IDO.
Prostaglandin E2 Inhibits Alveolar Macrophage Phagocytosis through an E-Prostanoid 2 Receptor-Mediated Increase in Intracellular Cyclic AMP
Authors: Aronoff David M. , Canetti Claudio , Peters-Golden Marc 
Published: April 2014

Abstract
Prostaglandin E2 is a potent lipid mediator of inflammation that effects changes in cell functions through ligation of four distinct G protein-coupled receptors (E-prostanoid (EP)1, EP2, EP3, and EP4). During pneumonia, PGE2 production is enhanced. In the present study, we sought to assess the effect of endogenously produced and exogenously added PGE2 on FcRγ-mediated phagocytosis of bacterial pathogens by alveolar macrophages (AMs), which are critical participants in lung innate immunity. We also sought to characterize the EP receptor signaling pathways responsible for these effects. PGE2 (1–1000 nM) dose-dependently suppressed the phagocytosis by rat AMs of IgG-opsonized erythrocytes, immune serum-opsonized Klebsiella pneumoniae, and IgG-opsonized Escherichia coli. Conversely, phagocytosis was stimulated by pretreatment with the cyclooxygenase inhibitor indomethacin. PGE2 suppression of phagocytosis was associated with enhanced intracellular cAMP production. Experiments using both forskolin (adenylate cyclase activator) and rolipram (phosphodiesterase IV inhibitor) confirmed the inhibitory effect of cAMP stimulation. Immunoblot analysis of rat AMs identified expression of only EP2 and EP3 receptors. The selective EP2 agonist butaprost, but neither the EP1/EP3 agonist sulprostone nor the EP4-selective agonist ONO-AE1-329, mimicked the effects of PGE2 on phagocytosis and cAMP stimulation. Additionally, the EP2 antagonist AH-6809 abrogated the inhibitory effects of both PGE2 and butaprost. We confirmed the specificity of our results by showing that AMs from EP2-deficient mice were resistant to the inhibitory effects of PGE2. Our data support a negative regulatory role for PGE2 on the antimicrobial activity of AMs, which has important implications for future efforts to prevent and treat bacterial pneumonia.
Helicobacter pylori Arginase Inhibits T Cell Proliferation and Reduces the Expression of the TCR ζ-Chain (CD3ζ)
Authors: Zabaleta Jovanny , McGee David J. , Zea Arnold H. , Hernández Claudia P. , Rodriguez Paulo C. , Sierra Rosa A. , Correa Pelayo , Ochoa Augusto C. 
Published: April 2014

Abstract
Helicobacter pylori infects approximately half the human population. The outcomes of the infection range from gastritis to gastric cancer and appear to be associated with the immunity to H. pylori. Patients developing nonatrophic gastritis present a Th1 response without developing protective immunity, suggesting that this bacterium may have mechanisms to evade the immune response of the host. Several H. pylori proteins can impair macrophage and T cell function in vitro through mechanisms that are poorly understood. We tested the effect of H. pylori extracts and live H. pylori on Jurkat cells and freshly isolated human normal T lymphocytes to identify possible mechanisms by which the bacteria might impair T cell function. Jurkat cells or activated T lymphocytes cultured with an H. pylori sonicate had a reduced proliferation that was not caused by T cell apoptosis or impairment in the early T cell signaling events. Instead, both the H. pylori sonicate and live H. pylori induced a decreased expression of the CD3ζ-chain of the TCR. Coculture of live H. pylori with T cells demonstrated that the wild-type strain, but not the arginase mutant rocF(−), depleted l-arginine and caused a decrease in CD3ζ expression. Furthermore, arginase inhibitors reversed these events. These results suggest that H. pylori arginase is not only important for urea production, but may also impair T cell function during infection.
Identification of Peptides That Antagonize Formyl Peptide Receptor-Like 1-Mediated Signaling
Authors: Bae Yoe-Sik , Lee Ha Young , Jo Eun Jin , Kim Jung Im , Kang Hyun-Kyu , Ye Richard D. , Kwak Jong-Young , Ryu Sung Ho 
Published: April 2014

Abstract
Formyl peptide receptor-like 1 (FPRL1) is an important classical chemoattractant receptor that is expressed in phagocytic cells in the peripheral blood and brain. Recently, various novel agonists have been identified from several origins, such as host-derived molecules. Activation of FPRL1 is closely related to inflammatory responses in the host defense mechanism and neurodegenerative disorders. In the present study we identified several novel peptides by screening hexapeptide libraries that inhibit the binding of one of FPRL1’s agonists (Trp-Lys-Tyr-Met-Val-d-Met-CONH2 (WKYMVm)) to its specific receptor, FPRL1, in RBL-2H3 cells. Among the novel peptides, Trp-Arg-Trp-Trp-Trp-Trp-CONH2 (WRWWWW (WRW4)) showed the most potent activity in terms of inhibiting WKYMVm binding to FPRL1. We also found that WRW4 inhibited the activation of FPRL1 by WKYMVm, resulting in the complete inhibition of the intracellular calcium increase, extracellular signal-regulated kinase activation, and chemotactic migration of cells toward WKYMVm. For the receptor specificity of WRW4 to the FPR family, we observed that WRW4 specifically inhibit the increase in intracellular calcium by the FPRL1 agonists MMK-1, amyloid β42 (Aβ42) peptide, and F peptide, but not by the FPR agonist, fMLF. To investigate the effect of WRW4 on endogenous FPRL1 ligand-induced cellular responses, we examined its effect on Aβ42 peptide in human neutrophils. Aβ42 peptide-induced superoxide generation and chemotactic migration of neutrophils were inhibited by WRW4, which also completely inhibited the internalization of Aβ42 peptide in human macrophages. WRW4 is the first specific FPRL1 antagonist and is expected to be useful in the study of FPRL1 signaling and in the development of drugs against FPRL1-related diseases.
Rac and Protein Kinase C-δ Regulate ERKs and Cytosolic Phospholipase A2 in FcεRI Signaling to Cysteinyl Leukotriene Synthesis in Mast Cells
Authors: Cho Sung-Hoon , You Hye-Jin , Woo Chang-Hoon , Yoo Yung-Joon , Kim Jae-Hong 
Published: April 2014

Abstract
Although cysteinyl leukotrienes (cysLTs) are known to be principal inflammatory lipid mediators released from IgE-stimulated mast cells, the signaling mechanisms involved in the synthesis of cysLTs remain largely unknown. In the present study, therefore, we investigated the signaling pathway by which IgE induces cysLTs synthesis after binding to its high affinity receptor (FcεRI) in RBL-2H3 mast cells. We found that IgE-induced cysLT synthesis is completely abolished in RBL-2H3Rac-N17 cells, a stable cell line expressing RacN17, a dominant negative Rac1 mutant; conversely, synthesis was enhanced in cells expressing RacV12, a constitutively active Rac1 mutant, suggesting that Rac1 is a key mediator of IgE signaling to cysLT synthesis. Further analysis aimed at identifying mediators downstream of Rac1 revealed that pretreating cells with a protein kinase C-δ (PKC-δ) inhibitor or infection with an adenoviral vector harboring a dominant negative PKC-δ mutant significantly attenuates IgE-induced ERKs phosphorylation, cytosolic phospholipase A2 phosphorylation/translocation, and cysLT synthesis. In addition, the expression of RacN17 blocked PKC-δ translocation and impaired the phosphorylation of ERKs and cytosolic phospholipase A2 otherwise elicited by IgE stimulation. Taken together these results suggest that PKC-δ also plays a critical mediatory role in the IgE signaling pathway leading to cysLT synthesis, acting downstream of Rac1. Finally, the physiological significance of PKC-δ in the IgE signaling pathway was demonstrated in an Ag (OVA)-challenged in vivo mouse model, in which induced levels of cysLTs and airway responsiveness in lung airways were significantly diminished by prior i.p. injection of a PKC-δ inhibitor.
Distinct Activation Signals Determine whether IL-21 Induces B Cell Costimulation, Growth Arrest, or Bim-Dependent Apoptosis
Authors: Jin Haoli , Carrio Roberto , Yu Aixin , Malek Thomas R. 
Published: April 2014

Abstract
IL-21 costimulates B cell proliferation and cooperatively with IL-4 promotes T cell-dependent Ab responses. Somewhat paradoxically, IL-21 also induces apoptosis of B cells. The present study was undertaken to more precisely define the expression of the IL-21R, using a novel mAb, and the circumstances by which IL-21 promotes B cell growth vs death. The IL-21R was first detected during T and B cell development, such that this receptor is expressed by all mature lymphocytes. The IL-21R was further up-regulated after B and T activation, with the highest expression by activated B cells. Functional studies demonstrated that IL-21 substantially inhibited proliferation and induced Bim-dependent apoptosis for LPS or CpG DNA-activated B cells. In contrast, IL-21 induced both costimulation and apoptosis for anti-CD40-stimulated B cells, whereas IL-21 primarily costimulated B cells activated by anti-IgM or anti-IgM plus anti-CD40. Upon blocking apoptosis using C57BL/6 Bim-deficient or Bcl-2 transgenic B cells, IL-21 readily costimulated responses to anti-CD40 while proliferation to LPS was still inhibited. Engagement of CD40 or the BCR plus CD40 prevented the inhibitory effect by IL-21 for LPS-activated B cells. Collectively, these data indicate that there are three separable outcomes for IL-21-stimulated B cells: apoptosis, growth arrest, or costimulation. We favor a model in which IL-21 promotes B cell maturation during a productive T cell-dependent B cell response, while favoring growth arrest and apoptosis for nonspecifically or inappropriately activated B cells.
Age-Associated Change in the Frequency of Memory CD4+ T Cells Impairs Long Term CD4+ T Cell Responses to Influenza Vaccine
Authors: Kang Insoo , Hong Myung Sun , Nolasco Helena , Park Sung Hwan , Dan Jin Myung , Choi Jin-Young , Craft Joe 
Published: April 2014

Abstract
We investigated the relationship of memory CD4+ T cells with the evolution of influenza virus-specific CD4+ T cell responses in healthy young and elderly people. Elderly individuals had a similar frequency of CD69+CD4+ T cells producing IFN-γ and TNF-α at 1 wk, but a lower frequency of these CD4+ T cells at 3 mo after influenza vaccination. Although the elderly had a higher frequency of central memory (CM; CCR7+CD45RA−) CD4+ T cells, they had a significantly lower frequency of effector memory (EM; CCR7−CD45RA−) CD4+ T cells, and the frequency of the latter memory CD4+ T cells positively correlated with the frequency of influenza virus-specific CD69+CD4+ T cells producing IFN-γ at 3 mo. These findings indicate that the elderly have an altered balance of memory CD4+ T cells, which potentially affects long term CD4+ T cell responses to the influenza vaccine. Compared with the young, the elderly had decreased serum IL-7 levels that positively correlated with the frequency of EM cells, which suggests a relation between IL-7 and decreased EM cells. Thus, although the healthy elderly mount a level of CD4+ T cell responses after vaccination comparable to that observed in younger individuals, they fail to maintain or expand these responses. This failure probably stems from the alteration in the frequency of CM and EM CD4+ T cells in the elderly that is related to alteration in IL-7 levels. These findings raise an important clinical question about whether the vaccination strategy in the elderly should be modified to improve cellular immune responses.
T Follicular Helper Cells Express a Distinctive Transcriptional Profile, Reflecting Their Role as Non-Th1/Th2 Effector Cells That Provide Help for B Cells
Authors: Chtanova Tatyana , Tangye Stuart G. , Newton Rebecca , Frank Nita , Hodge Martin R. , Rolph Michael S. , Mackay Charles R. 
Published: April 2014

Abstract
Effector T cell responses have long been viewed in the context of the Th1/Th2 paradigm. Recently, a third major subset of nonpolarized effector T cells that provides help to B cells has been identified. These T cells, termed T follicular helper (TFH) cells, home to the B cell areas of secondary lymphoid tissue, through interactions mediated via the chemokine receptor CXCR5 and its ligand CXCL13. Affymetrix microarrays were used to identify transcription factors, cytokines, and cell surface molecules that underlie the differentiation pathways and functional properties of the TFH subset. The transcriptional profile of human CXCR5+ TFH cells was compared with that of Th1 and Th2 cells, which enabled the identification of numerous genes expressed preferentially by TFH cells, over the other effector subsets. Certain TFH genes were also expressed by B cells and thus appear to be particularly relevant for humoral immunity. Abs were used to confirm the expression of several factors. In particular, CD84 and CD200, the cytokine IL-21, and the transcription factor BCL6 were all strongly associated with TFH cells. Gene microarrays reveal a highly distinctive transcriptional profile for a third subset of effector T cells that differs markedly from Th1 and Th2 cells.
Lymphotoxin and TNF Produced by B Cells Are Dispensable for Maintenance of the Follicle-Associated Epithelium but Are Required for Development of Lymphoid Follicles in the Peyer’s Patches
Authors: Tumanov Alexei V. , Kuprash Dmitry V. , Mach Julie A. , Nedospasov Sergei A. , Chervonsky Alexander V. 
Published: April 2014

Abstract
Organogenesis of Peyer‘s patches (PP), follicle-associated epithelium, and M cells is impaired in mice lacking B cells. At the same time, lymphotoxin (LT) and TNF are known to be critical for the development of PP. To directly address the function of LT and TNF expressed by B cells in the maintenance of PP structure, we studied the de novo formation of PP in B cell-deficient mice after the transfer of bone marrow from mice with targeted mutations in LT, TNF, or their combinations. We found that although the compartmentalization of T and B cell zones and development of follicular dendritic cells were affected by the lack of B cell-derived LT and TNF, the development of follicle-associated epithelium and M cells in PP was completely independent of LT/TNF production by B cells.