bluuebunny/crossref_metadata_2025_split huggingface dataset:
Emergence of a CD4+CD28− Granzyme B+, Cytomegalovirus-Specific T Cell Subset after Recovery of Primary Cytomegalovirus Infection
Authors: van Leeuwen Ester M. M. , Remmerswaal Ester B. M. , Vossen Mireille T. M. , Rowshani Ajda T. , Wertheim-van Dillen Pauline M. E. , van Lier René A. W. , ten Berge Ineke J. M. 
Published: April 2014

AbstractCytotoxic CD4+CD28− T cells form a rare subset in human peripheral blood. The presence of CD4+CD28− cells has been associated with chronic viral infections, but how these particular cells are generated is unknown. In this study, we show that in primary CMV infections, CD4+CD28− T cells emerge just after cessation of the viral load, indicating that infection with CMV triggers the formation of CD4+CD28− T cells. In line with this, we found these cells only in CMV-infected persons. CD4+CD28− cells had an Ag-primed phenotype and expressed the cytolytic molecules granzyme B and perforin. Importantly, CD4+CD28− cells were to a large extent CMV-specific because proliferation was only induced by CMV-Ag, but not by recall Ags such as purified protein derivative or tetanus toxoid. CD4+CD28− cells only produced IFN-γ after stimulation with CMV-Ag, whereas CD4+CD28+ cells also produced IFN-γ in response to varicella-zoster virus and purified protein derivative. Thus, CD4+CD28− T cells emerge as a consequence of CMV infection.
De Novo Synthesized RelB Mediates TNF-Induced Up-Regulation of the Human Polymeric Ig Receptor
Authors: Schjerven Hilde , Tran Thien N. , Brandtzaeg Per , Johansen Finn-Eirik 
Published: April 2014

Abstract
Secretory Abs, which operate in a principally noninflammatory fashion, constitute the first line of acquired immune defense of mucosal surfaces. Such Abs are generated by polymeric Ig receptor (pIgR)-mediated export of dimeric IgA and pentameric IgM. TNF activates a proinflammatory gene repertoire in mucosal epithelial cells and also enhances pIgR expression. In this study we show that TNF-induced up-regulation of the human pIgR critically depends on an NF-κB site and flanking sequences within a 204-bp region of the first intron in the pIgR gene, a region largely overlapping with a recently characterized IL-4-responsive enhancer. The intronic NF-κB site was rapidly bound by NF-κB p65/p50 heterodimers present in nuclear extracts after TNF treatment of HT-29 cells, but a more delayed binding of RelB agreed better with the slow, protein synthesis-dependent, transcriptional activation of the pIgR gene. Overexpression of NF-κB p65 caused transient up-regulation of a pIgR-derived reporter gene, whereas overexpression of RelB showed a stronger and more sustained effect. Finally, we demonstrated that inhibition of endogenous RelB by RNA interference severely reduced the TNF responsiveness of our pIgR-derived reporter gene. Thus, TNF-induced signaling pathways required for up-regulated pIgR expression appear to differ from those of the proinflammatory gene repertoire.
LacdiNAc-Glycans Constitute a Parasite Pattern for Galectin-3-Mediated Immune Recognition
Authors: van den Berg Timo K. , Honing Henk , Franke Niels , van Remoortere Alexandra , Schiphorst Wietske E. C. M. , Liu Fu-Tong , Deelder André M. , Cummings Richard D. , Hokke Cornelis H. , van Die Irma 
Published: April 2014

Abstract
Although Galβ1–4GlcNAc (LacNAc) moieties are the most common constituents of N-linked glycans on vertebrate proteins, GalNAcβ1–4GlcNAc (LacdiNAc, LDN)-containing glycans are widespread in invertebrates, such as helminths. We postulated that LDN might be a molecular pattern for recognition of helminth parasites by the immune system. Using LDN-based affinity chromatography and mass spectrometry, we have identified galectin-3 as the major LDN-binding protein in macrophages. By contrast, LDN binding was not observed with galectin-1. Surface plasmon resonance (SPR) analysis and a solid phase binding assay demonstrated that galectin-3 binds directly to neoglycoconjugates carrying LDN glycans. In addition, galectin-3 bound to Schistosoma mansoni soluble egg Ags and a mAb against the LDN glycan inhibited this binding, suggesting that LDN glycans within S. mansoni soluble egg Ags contribute to galectin-3 binding. Immunocytochemistry demonstrated high levels of galectin-3 in liver granulomas of S. mansoni-infected hamsters, and a colocalization of galectin-3 and LDN glycans was observed on the parasite eggshells. Finally, we demonstrate that galectin-3 can mediate recognition and phagocytosis of LDN-coated particles by macrophages. These findings provide evidence that LDN-glycans constitute a parasite pattern for galectin-3-mediated immune recognition.
MAdCAM-1 Expressing Sacral Lymph Node in the Lymphotoxin β-Deficient Mouse Provides a Site for Immune Generation Following Vaginal Herpes Simplex Virus-2 Infection
Authors: Soderberg Kelly A. , Linehan Melissa M. , Ruddle Nancy H. , Iwasaki Akiko 
Published: April 2014

Abstract
The members of the lymphotoxin (LT) family of molecules play a critical role in lymphoid organogenesis. Whereas LTα-deficient mice lack all lymph nodes and Peyer’s patches, mice deficient in LTβ retain mesenteric lymph nodes and cervical lymph nodes, suggesting that an LTβ-independent pathway exists for the generation of mucosal lymph nodes. In this study, we describe the presence of a lymph node in LTβ-deficient mice responsible for draining the genital mucosa. In the majority of LTβ-deficient mice, a lymph node was found near the iliac artery, slightly misplaced from the site of the sacral lymph node in wild-type mice. The sacral lymph node of the LTβ-deficient mice, as well as that of the wild-type mice, expressed the mucosal addressin cell adhesion molecule-1 similar to the mesenteric lymph node. Following intravaginal infection with HSV type 2, activated dendritic cells capable of stimulating a Th1 response were found in this sacral lymph node. Furthermore, normal HSV-2-specific IgG responses were generated in the LTβ-deficient mice following intravaginal HSV-2 infection even in the absence of the spleen. Therefore, an LTβ-independent pathway exists for the development of a lymph node associated with the genital mucosa, and such a lymph node serves to generate potent immune responses against viral challenge.
Innate Immune Responses to Rhodococcus equi
Authors: Darrah Patricia A. , Monaco Maria Chiara G. , Jain Shruti , Hondalus Mary K. , Golenbock Douglas T. , Mosser David M. 
Published: April 2014

Abstract
We examined innate immune responses to the intracellular bacterium Rhodococcus equi and show that infection of macrophages with intact bacteria induced the rapid translocation of NF-κB and the production of a variety of proinflammatory mediators, including TNF, IL-12, and NO. Macrophages from mice deficient in MyD88 failed to translocate NF-KB and produced virtually no cytokines in response to R. equi infection, implicating a TLR pathway. TLR4 was not involved in this response, because C3H/HeJ macrophages were fully capable of responding to R. equi infection, and because RAW-264 cells transfected with a dominant negative form of TLR4 responded normally to infection by R. equi. A central role for TLR2 was identified. A TLR2 reporter cell was activated by R. equi, and RAW-264 cells transfected with a dominant negative TLR2 exhibited markedly reduced cytokine responses to R. equi. Moreover, macrophages from TLR2−/− mice exhibited diminished cytokine responses to R. equi. The role of the surface-localized R. equi lipoprotein VapA (virulence-associated protein A), in TLR2 activation was examined. Purified rVapA activated a TLR2-specific reporter cell, and it induced the maturation of dendritic cells and the production of cytokines from macrophages. Importantly, TLR2−/−-deficient but not TLR4−/−-deficient mice were found to be compromised in their ability to clear a challenge with virulent R. equi. We conclude that the efficient activation of innate immunity by R. equi may account for the relative lack of virulence of this organism in immunocompetent adults.
Wheat Gluten Causes Dendritic Cell Maturation and Chemokine Secretion
Authors: Nikulina Marina , Habich Christiane , Flohé Stefanie B. , Scott Fraser W. , Kolb Hubert 
Published: April 2014

Abstract
Wheat gluten causes gut inflammation in genetically predisposed individuals. We tested the hypothesis that wheat gluten is not only a target of adaptive immunity, but also modulates the function of APC. Dendritic cells (DC) derived from the bone marrow of BALB/c mice were exposed to chymotrypsin-treated wheat gluten. This induced DC maturation as estimated by all surface markers tested (MHC class II, CD40, CD54, and CD86). The effect was dose dependent, and, at 100 μg/ml gluten matched that caused by 10 ng/ml LPS. A role of endotoxin contamination was ruled out by demonstrating the resistance of wheat gluten effects to LPS antagonist polymyxin B. DC from LPS nonresponder strain C3H/HeJ were affected by wheat gluten, but not by LPS. Proteinase K-digested wheat gluten was unable to stimulate DC maturation. Wheat gluten induced a unique secretion pattern of selected cytokines and chemokines in DC. Classic pro- or anti-inflammatory mediators were not produced, in contrast to LPS. Rather, chemokines MIP-2 and keratinocyte-derived cytokine were secreted in large amounts. We conclude that wheat gluten lowers the threshold for immune responses by causing maturation of APC, by attracting leukocytes and increasing their reactivity state. In the presence of an appropriate genetic predisposition, this is expected to increase the risk of adverse immune reactions to wheat gluten or to other Ags presented.
Role of IgA versus IgG in the Control of Influenza Viral Infection in the Murine Respiratory Tract
Authors: Renegar Kathryn B. , Small Parker A. , Boykins Lou G. , Wright Peter F. 
Published: April 2014

Abstract
The roles of IgG and secretory IgA in the protection of the respiratory tract (RT) against influenza infection remain unclear. Passive immunization with Ab doses resulting in serum IgG anti-influenza virus Ab titers far in excess of those observed in immune mice has compounded the problem. We compared the effects of i.v. anti-influenza virus IgG and i.v. anti-influenza virus polymeric IgA (pIgA) mAb administered in amounts designed to replicate murine convalescent serum or nasal Ab titers, respectively. A serum anti-influenza virus IgG titer 2.5 times the normal convalescent serum anti-influenza virus IgG titer was required for detectible Ab transudation into nasal secretions, and a serum IgG titer 7 times normal was needed to lower nasal viral shedding by 98%. Anti-influenza virus pIgA at a nasal Ab titer comparable to that seen in convalescent mice eliminated nasal viral shedding. The RT of influenza-infected pIgA- or IgG-protected mice were studied by scanning electron microscopy. Only pIgA was found to prevent virally induced pathology in the upper RT, suggesting that IgG did not prevent viral infection of the nose, but neutralized newly replicated virus after infection had been initiated. In contrast, IgG, but not pIgA, was found to prevent viral pathology in the murine lung. Our results help to resolve the controversy of IgA- vs IgG-mediated protection of the RT; both Abs are important, with plasma IgG Ab serving as the back-up for secretory IgA-mediated protection in the nasal compartment, and IgG being the dominant Ab in protection of the lung.
Neutrophil Involvement in Cross-Priming CD8+ T Cell Responses to Bacterial Antigens
Authors: Tvinnereim Amy R. , Hamilton Sara E. , Harty John T. 
Published: April 2014

Abstract
Substantial CD8+ T cell responses are generated after infection of mice with recombinant Listeria monocytogenes strains expressing a model epitope (lymphocytic choriomeningitis virus NP118–126) in secreted and nonsecreted forms. L. monocytogenes gains access to the cytosol of infected cells, where secreted Ags can be accessed by the endogenous MHC class I presentation pathway. However, the route of presentation of the nonsecreted Ag in vivo remains undefined. In this study we show that neutrophil-enriched peritoneal exudate cells from L. monocytogenes-infected mice can serve as substrates for in vitro cross-presentation of both nonsecreted and secreted Ag by dendritic cells as well as for in vivo cross-priming of CD8+ T cells. In addition, specific neutrophil depletion in vivo by low dose treatment with either of two Ly6G-specific mAb substantially decreased the relative CD8+ T cell response against the nonsecreted, but not the secreted, Ag compared with control Ab-treated mice. Thus, neutrophils not only provide rapid innate defense against infection, but also contribute to shaping the specificity and breadth of the CD8+ T cell response. In addition, cross-presentation of bacterial Ags from neutrophils may explain how CD8+ T cell responses are generated against Ags from extracellular bacterial pathogens.
Cyclooxygenase (COX)-2 Inhibitor Celecoxib Abrogates TNF-Induced NF-κB Activation through Inhibition of Activation of IκBα Kinase and Akt in Human Non-Small Cell Lung Carcinoma: Correlation with Suppression of COX-2 Synthesis
Authors: Shishodia Shishir , Koul Dimpy , Aggarwal Bharat B. 
Published: April 2014

Abstract
The cyclooxygenase 2 (COX-2) inhibitor celecoxib (also called celebrex), approved for the treatment of colon carcinogenesis, rheumatoid arthritis, and other inflammatory diseases, has been shown to induce apoptosis and inhibit angiogenesis. Because NF-κB plays a major role in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation, we postulated that celecoxib modulates NF-κB. In the present study, we investigated the effect of this drug on the activation of NF-κB by a wide variety of agents. We found that celecoxib suppressed NF-κB activation induced by various carcinogens, including TNF, phorbol ester, okadaic acid, LPS, and IL-1β. Celecoxib inhibited TNF-induced IκBα kinase activation, leading to suppression of IκBα phosphorylation and degradation. Celecoxib suppressed both inducible and constitutive NF-κB without cell type specificity. Celecoxib also suppressed p65 phosphorylation and nuclear translocation. Akt activation, which is required for TNF-induced NF-κB activation, was also suppressed by this drug. Celecoxib also inhibited the TNF-induced interaction of Akt with IκBα kinase (IKK). Celecoxib abrogated the NF-κB-dependent reporter gene expression activated by TNF, TNF receptor, TNF receptor-associated death domain, TNF receptor-associated factor 2, NF-κB-inducing kinase, and IKK, but not that activated by p65. The COX-2 promoter, which is regulated by NF-κB, was also inhibited by celecoxib, and this inhibition correlated with suppression of TNF-induced COX-2 expression. Besides NF-κB, celecoxib also suppressed TNF-induced JNK, p38 MAPK, and ERK activation. Thus, overall, our results indicate that celecoxib inhibits NF-κB activation through inhibition of IKK and Akt activation, leading to down-regulation of synthesis of COX-2 and other genes needed for inflammation, proliferation, and carcinogenesis.
Heme Inhibits Human Neutrophil Apoptosis: Involvement of Phosphoinositide 3-Kinase, MAPK, and NF-κB
Authors: Arruda Maria Augusta , Rossi Adriano G. , de Freitas Marta S. , Barja-Fidalgo Christina , Graça-Souza Aurélio V. 
Published: April 2014

Abstract
High levels of free heme are found in pathological states of increased hemolysis, such as sickle cell disease, malaria, and ischemia reperfusion. The hemolytic events are often associated with an inflammatory response that usually turns into chronic inflammation. We recently reported that heme is a proinflammatory molecule, able to induce neutrophil migration, reactive oxygen species generation, and IL-8 expression. In this study, we show that heme (1–50 μM) delays human neutrophil spontaneous apoptosis in vitro. This effect requires heme oxygenase activity, and depends on reactive oxygen species production and on de novo protein synthesis. Inhibition of ERK and PI3K pathways abolished heme-protective effects upon human neutrophils, suggesting the involvement of the Ras/Raf/MAPK and PI3K pathway on this effect. Confirming the involvement of these pathways in the modulation of the antiapoptotic effect, heme induces Akt phosphorylation and ERK-2 nuclear translocation in neutrophils. Futhermore, inhibition of NF-κB translocation reversed heme antiapoptotic effect. NF-κB (p65 subunit) nuclear translocation and IκB degradation were also observed in heme-treated cells, indicating that free heme may regulate neutrophil life span modulating signaling pathways involved in cell survival. Our data suggest that free heme associated with hemolytic episodes might play an important role in the development of chronic inflammation by interfering with the longevity of neutrophils.
Different Domains of Pseudomonas aeruginosa Exoenzyme S Activate Distinct TLRs
Authors: Epelman Slava , Stack Danuta , Bell Chris , Wong Erica , Neely Graham G. , Krutzik Stephan , Miyake Kensuke , Kubes Paul , Zbytnuik Lori D. , Ma Ling Ling , Xie Xiaobin , Woods Donald E. , Mody Christopher H. 
Published: April 2014

Abstract
Some bacterial products possess multiple immunomodulatory effects and thereby complex mechanisms of action. Exogenous administration of an important Pseudomonas aeruginosa virulence factor, exoenzyme S (ExoS) induces potent monocyte activation leading to the production of numerous proinflammatory cytokines and chemokines. However, ExoS is also injected directly into target cells, inducing cell death through its multiple effects on signaling pathways. This study addresses the mechanisms used by ExoS to induce monocyte activation. Exogenous administration resulted in specific internalization of ExoS via an actin-dependent mechanism. However, ExoS-mediated cellular activation was not inhibited if internalization was blocked, suggesting an alternate mechanism of activation. ExoS bound a saturable and specific receptor on the surface of monocytic cells. ExoS, LPS, and peptidoglycan were all able to induce tolerance and cross-tolerance to each other suggesting the involvement of a TLR in ExoS-recognition. ExoS activated monocytic cells via a myeloid differentiation Ag-88 pathway, using both TLR2 and the TLR4/MD-2/CD14 complex for cellular activation. Interestingly, the TLR2 activity was localized to the C-terminal domain of ExoS while the TLR4 activity was localized to the N-terminal domain. This study provides the first example of how different domains of the same molecule activate two TLRs, and also highlights the possible overlapping pathophysiological processes possessed by microbial toxins.
Phenyl Methimazole Inhibits TNF-α-Induced VCAM-1 Expression in an IFN Regulatory Factor-1-Dependent Manner and Reduces Monocytic Cell Adhesion to Endothelial Cells
Authors: Dagia Nilesh M. , Harii Norikazu , Meli Antonella E. , Sun Xiaolu , Lewis Christopher J. , Kohn Leonard D. , Goetz Douglas J. 
Published: April 2014

AbstractProinflammatory cytokine (e.g., TNF-α)-induced expression of endothelial cell adhesion molecules (ECAMs) on the lumenal surface of the vascular endothelium and a consequent increase in leukocyte adhesion are key aspects of pathological inflammation. A promising therapeutic approach to diminish aberrant leukocyte adhesion is, therefore, to inhibit cytokine-induced ECAM expression at the transcription level. Several studies suggest that methimazole, a compound used clinically to treat autoimmune diseases, such as Graves’ disease, may also diminish pathological inflammation by suppressing ECAM expression. In this study we probed the hypothesis that a derivative of methimazole, phenyl methimazole (compound 10), can reduce cytokine-induced ECAM expression and consequent leukocyte adhesion. We found that compound 10 1) dramatically inhibits TNF-α-induced VCAM-1 mRNA and protein expression in human aortic endothelial cells (HAEC), has a relatively modest inhibitory effect on TNF-α induced E-selectin expression and has no effect on ICAM-1 expression; 2) significantly reduces TNF-α-induced monocytic (U937) cell adhesion to HAEC under in vitro flow conditions similar to that present in vivo; 3) inhibits TNF-α-induced IFN regulatory factor-1 binding to VCAM-1 promoter; and 4) reduces TNF-α-induced IRF-1 expression in HAEC. Combined, the results indicate that phenyl methimazole can reduce TNF-α-induced VCAM-1 expression in an IFN regulatory factor-1-dependent manner and that this contributes significantly to reduced monocytic cell adhesion to TNF-α-activated HAEC.
Platelet Factor 4/CXCL4 Induces Phagocytosis and the Generation of Reactive Oxygen Metabolites in Mononuclear Phagocytes Independently of Gi Protein Activation or Intracellular Calcium Transients
Authors: Pervushina Olga , Scheuerer Barbara , Reiling Norbert , Behnke Lars , Schröder Jens.-M. , Kasper Brigitte , Brandt Ernst , Bulfone-Paus Silvia , Petersen Frank 
Published: April 2014

Abstract
Platelet factor 4 (PF-4), a platelet-derived CXC chemokine, is known to prevent human monocytes from apoptosis and to promote differentiation of these cells into HLA-DR− macrophages. In this study, we investigated the role of PF-4 in the control of acute monocyte proinflammatory responses involved in the direct combat of microbial invaders. We show that PF-4 increases monocyte phagocytosis and provokes a strong formation of oxygen radicals but lacks a chemotactic activity in these cells. Compared with FMLP, PF-4-induced oxidative burst was later in its onset but was remarkably longer in its duration (lasting for up to 60 min). Furthermore, in PF-4-prestimulated cells, FMLP- as well as RANTES-induced burst responses became synergistically enhanced. As we could show, PF-4-mediated oxidative burst in monocytes does not involve Gi proteins, elevation of intracellular free calcium concentrations, or binding to CXCR3B, a novel PF-4 receptor recently discovered on endothelial cells. Moreover, we found that PF-4 acts on macrophages in a dual manner. On the one hand, very similar to GM-CSF or M-CSF, PF-4 treatment of monocytes generates macrophages with a high capacity for unspecific phagocytosis. On the other hand, short term priming of GM-CSF-induced human macrophages with PF-4 substantially increases their capability for particle ingestion and oxidative burst. A comparable effect was also observed in murine bone marrow-derived macrophages, indicating cross-reactivity of human PF-4 between both species. Taken together, PF-4 may play a crucial role in the induction and maintenance of an unspecific immune response.
Liver-Expressed Chemokine/CC Chemokine Ligand 16 Attracts Eosinophils by Interacting with Histamine H4 Receptor
Authors: Nakayama Takashi , Kato Yoshiko , Hieshima Kunio , Nagakubo Daisuke , Kunori Yuichi , Fujisawa Takao , Yoshie Osamu 
Published: April 2014

Abstract
Liver-expressed chemokine (LEC)/CCL16 is a human CC chemokine that is constitutively expressed by the liver parenchymal cells and present in the normal plasma at high concentrations. Previous studies have shown that CCL16 is a low-affinity ligand for CCR1, CCR2, CCR5, and CCR8 and attracts monocytes and T cells. Recently, a novel histamine receptor termed type 4 (H4) has been identified and shown to be selectively expressed by eosinophils and mast cells. In this study, we demonstrated that CCL16 induced pertussis toxin-sensitive calcium mobilization and chemotaxis in murine L1.2 cells expressing H4 but not those expressing histamine receptor type 1 (H1) or type 2 (H2). CCL16 bound to H4 with a Kd of 17 nM. By RT-PCR, human and mouse eosinophils express H4 but not H3. Accordingly, CCL16 induced efficient migratory responses in human and mouse eosinophils. Furthermore, the responses of human and mouse eosinophils to CCL16 were effectively suppressed by thioperamide, an antagonist for H3 and H4. Intravenous injection of CCL16 into mice induced a rapid mobilization of eosinophils from bone marrow to peripheral blood, which was also suppressed by thioperamide. Collectively, CCL16 is a novel functional ligand for H4 and may have a role in trafficking of eosinophils.