bluuebunny/crossref_metadata_2025_split huggingface dataset:
Requirement of a Novel Upstream Response Element in Respiratory Syncytial Virus-Induced IL-8 Gene Expression
Authors: Casola Antonella , Garofalo Roberto P. , Jamaluddin Mohammad , Vlahopoulos Spiros , Brasier Allan R. 
Published: April 2014

Abstract
Respiratory syncytial virus (RSV) produces intense pulmonary inflammation, in part, through its ability to induce chemokine synthesis in infected airway epithelial cells. In this study, we compare mechanisms for induction of the CXC chemokine IL-8, in human type II alveolar (A549) cells by RSV infection and by stimulation with the cytokine TNF. Promoter deletion and mutagenesis experiments indicate that although the region from −99 to −54 nt is sufficient for TNF-induced IL-8 transcription, this region alone is not sufficient for RSV-induced IL-8 transcription. Instead, RSV requires participation of a previously unrecognized element, spanning from −162 to −132 nt, that we term the RSV response element (RSVRE), and a previously characterized element at −132 to −99 nt, containing an AP-1 binding site. RSV infection of A549 cells induces increased RSVRE- and AP-1-binding activities and increased synthesis of IFN regulatory factor-1 protein, which is present in the RSVRE-binding complex. These data confirm that the IL-8 gene enhancers are controlled in a stimulus-specific fashion and participation of distinct promoter elements is required to activate gene transcription. These observations are important for rational design of inhibitors of RSV-induced lung inflammation.
Differential Ability of Exogenous Chemotactic Agents to Disrupt Transendothelial Migration of Flowing Neutrophils
Authors: Luu N. Thin , Rainger G. Ed , Nash Gerard B. 
Published: April 2014

AbstractNeutrophils migrate through endothelium using an ordered sequence of adhesive interactions and activating signals. To investigate the consequences of disruption of this sequence, we characterized adhesion and migration of neutrophils perfused over HUVEC that had been treated with TNF-α for 4 h and evaluated changes caused by exogenously added chemotactic agents. When HUVEC were treated with 2 U/ml TNF, flowing neutrophils adhered, with the majority rolling and relatively few migrating through the monolayer. If fMLP, IL-8, zymosan-activated plasma (a source of activated complement factor C5a), epithelial cell-derived neutrophil-activating peptide (ENA-78), or growth-regulating oncogene, GRO-α, was perfused over these neutrophils, they stopped rolling and rapidly migrated over the monolayer, but did not penetrate it. When HUVEC were treated with 100 U/ml TNF, the majority of adherent neutrophils transmigrated. If neutrophils were treated with fMLP, IL-8, C5a, ENA-78, or GRO-α just before perfusion over this HUVEC, transmigration, but not adhesion, was abolished. However, when platelet-activating factor was used to activate neutrophils, migration through HUVEC treated with 100 U/ml TNF was not impaired, and migration through HUVEC treated with 2 U/ml TNF was actually increased. Transmigration required ligation of CXC chemokine receptor-2 on neutrophils, and differential desensitization of this receptor (e.g., by fMLP but not platelet-activating factor) may explain the pattern of disruption of migration. Thus, transmigration may require presentation of the correct activators in the correct sequence, and inappropriate activation (e.g., by systemic activators) could cause pathological accumulation of neutrophils in the vessel lumen.
Thiol-Reactive Metal Compounds Inhibit NF-κB Activation by Blocking IκB Kinase
Authors: Jeon Kye-Im , Jeong Jae-Yeon , Jue Dae-Myung 
Published: April 2014

AbstractGold compounds are used in the treatment of rheumatoid arthritis. NF-κB is a transcription factor implicated in the expression of many inflammatory genes. NF-κB is activated by signal-induced phosphorylation and subsequent degradation of inhibitory IκB (inhibitory protein that dissociates from NF-κB) proteins, and a multisubunit IκB kinase (IKK) has been identified previously. We tested the effect of various gold compounds on the activation of NF-κB and IKK in LPS-stimulated RAW 264.7 mouse macrophages. A lipophilic gold compound, auranofin, suppressed the LPS-induced increase of nuclear κB-binding activity, degradation of IκB proteins, and IKK activation. Auranofin also blocked IKK activation induced by TNF and PMA/ionomycin, suggesting that the target of auranofin action is common among these diverse signal pathways. In vitro IKK activity was suppressed by addition of hydrophilic gold compounds, such as aurothiomalate, aurothioglucose, and AuCl3. Other thiol-reactive metal ions such as zinc and copper also inhibited IKK activity in vitro, and induction of IKK in LPS-stimulated macrophages. In vitro IKK activity required the presence of reducing agent and was blocked by addition of thiol group-reactive agents. Two catalytic subunits of IKK complex, IKKα and IKKβ, were both inhibited by these thiol-modifying agents, suggesting the presence of a cysteine sulfhydryl group in these subunits, which is critical for enzyme activity. The antiinflammatory activity of gold compounds in the treatment of rheumatoid arthritis may depend on modification of this thiol group by gold.
Immune Complex and Fc Receptor-Mediated Augmentation of Antigen Presentation for in Vivo Th Cell Responses
Authors: Hamano Yuki , Arase Hisashi , Saisho Hiromitsu , Saito Takashi 
Published: April 2014

AbstractIt has recently been established that FcRs are involved in the triggering of type II and III inflammatory responses. Although FcR is not believed to be involved in the regulation of T cell function, the in vivo contribution of FcRs to T cell function still remains unclear. We analyzed in vivo responses of delayed-type hypersensitivity and proliferation of CD4+ T cells to Ags in FcRγ−/− mice lacking the expression and function of FcγRI, FcγRIII, and FcεRI. We found that the delayed-type hypersensitivity response in FcRγ−/− mice is significantly decreased compared with that in wild-type mice. Moreover, the secondary responses of proliferation and cytokine production as well as the Ab formation by CD4+ T cells from FcRγ−/− mice to Ag and normal APCs were also reduced. In contrast, in vitro primary T cell proliferative responses upon stimulation with anti-TCR Ab or MLR as well as in vivo primary response against staphylococcus enterotoxin B administration were not different between T cells from FcRγ−/− and wild-type mice. In addition, the Ag presentation function of APCs from unimmunized FcRγ−/− mice was normal. On the other hand, Ab-deficient mice also revealed impaired T cell responses. These results demonstrate that the defective T cell responses in FcRγ−/− mice were due to impaired Ag presentation during in vivo priming not to a defect in T cells. Therefore, they suggest that the FcRs on APCs mediate efficient priming of Th cell responses in vivo in an immune complex-dependent manner.
The Thyrotropin (Thyroid-Stimulating Hormone) Receptor Is Expressed on Murine Dendritic Cells and on a Subset of CD45RBhigh Lymph Node T Cells: Functional Role for Thyroid-Stimulating Hormone During Immune Activation
Authors: Bağriaçik E. Ümit , Klein John R. 
Published: April 2014

AbstractThyroid-stimulating hormone (TSH), a central neuroendocrine mediator of the hypothalamus-pituitary-thyroid axis, has been shown to affect various aspects of immunological development and function. To gain a better understanding of TSH involvement within the mammalian immune system, the expression and distribution of the TSH receptor (TSHr) has been studied by immunoprecipitation and by flow cytometric analyses. Using highly enriched populations of B cells, T cells, and dendritic cells, trace amounts of TSHr were precipitated from B cells and T cells, whereas high levels of TSHr were precipitated from the dendritic cell fraction. Flow cytometric analyses of TSHr expression on splenic and lymph node T cells revealed a major difference between those tissues in that only 2–3% of splenic T cells were TSHr+, whereas 10–20% of CD4+8− and CD4−8+ lymph node T cells expressed the TSHr, which was exclusively associated with CD45RBhigh cells and was not expressed during or after activation. The TSHr was not present on cells of the immune system during fetal or neonatal life. However, recombinant TSHβ was found to significantly enhance the phagocytic activity of dendritic cells from adult animals and to selectively augment IL-1β and IL-12 cytokine responses of dendritic cells following phagocytic activation. These findings identify a novel immune-endocrine bridge associated with professional APCs and naive T cells.
Melphalan and Other Anticancer Modalities Up-Regulate B7-1 Gene Expression in Tumor Cells
Authors: Sojka Dorothy K. , Donepudi Manjula , Bluestone Jeffrey A. , Mokyr Margalit B. 
Published: April 2014

AbstractIn this study, we show that administration of low-dose melphalan (l-PAM, l-phenylalanine mustard) to mice bearing a large MOPC-315 plasmacytoma led to a rapid up-regulation of B7-1 (CD80), but not B7-2 (CD86), expression on the surface of MOPC-315 tumor cells. This l-PAM-induced preferential up-regulation of B7-1 surface expression was due, at least in part, to a direct effect of l-PAM on the tumor cells, as in vitro exposure of MOPC-315 tumor cells to l-PAM led to the preferential up-regulation of B7-1 surface expression. Moreover, in vitro exposure of MOPC-315 tumor cells to two other anticancer modalities, γ-irradiation and mitomycin C, resulted in the preferential up-regulation of B7-1 surface expression. This effect was not restricted to MOPC-315 tumor cells, as preferential up-regulation of B7-1 surface expression was observed also following in vitro exposure of the P815 mastocytoma (that is negative for both B7-1 and B7-2 surface expression) to any of the three anticancer modalities. The up-regulation of B7-1 surface expression following in vitro exposure of tumor cells to l-PAM, γ-irradiation, or mitomycin C required de novo protein and RNA synthesis, and was associated with the accumulation of mRNA for B7-1 within 4–8 h, indicating that the regulation of B7-1 expression is at the RNA transcriptional level. These results have important implications for an additional immune-potentiating mechanism of these anticancer modalities in clinical setting.
Analysis of the Human Neonatal Thymus: Evidence for a Transient Thymic Involution
Authors: Varas Alberto , Jiménez Eva , Sacedón Rosa , Rodríguez-Mahou Margarita , Maroto Enrique , Zapata Agustín G. , Vicente Angeles 
Published: April 2014

AbstractThe neonatal period is marked by the impairment of the major components of both innate and adaptive immunity. We report a severe depletion of cortical CD4+CD8+ double-positive thymocytes in the human neonatal thymus. This drastic reduction in immature double-positive cells, largely provoked by an increased rate of cell death, could be observed as early as 1 day after birth, delaying the recovery of the normal proportion of this thymocyte subset until the end of the first month of postnatal life. Serum cortisol levels were not increased in newborn donors, indicating that the neonatal thymic involution is a physiological rather than a stress-associated pathological event occurring in the perinatal period. Newborn thymuses also showed increased proportions of both primitive CD34+CD1− precursor cells and mature TCRαβhighCD69−CD1−CD45RO+/RAdull and CD45ROdull/RA+ cells, which presumably correspond to recirculating T lymphocytes into the thymus. A notable reinforcement of the subcapsular epithelial cell layer as well as an increase in the intralobular extracellular matrix network accompanied modifications in the thymocyte population. Additionally neonatal thymic dendritic cells were found to be more effective than dendritic cells isolated from children’s thymuses at stimulating proliferative responses in allogeneic T cells. All these findings can account for several alterations affecting the peripheral pool of T lymphocytes in the perinatal period.
Fcγ Receptor IIB on Follicular Dendritic Cells Regulates the B Cell Recall Response
Authors: Qin Dahui , Wu Jiuhua , Vora Kalpit A. , Ravetch Jeffrey V. , Szakal Andras K. , Manser Tim , Tew John G. 
Published: April 2014

AbstractGeneration of the B cell recall response appears to involve interaction of Ag, in the form of an immune complex (IC) trapped on follicular dendritic cells (FDCs), with germinal center (GC) B cells. Thus, the expression of receptors on FDC and B cells that interact with ICs could be critical to the induction of an optimal recall response. FDCs in GCs, but not in primary follicles, express high levels of the IgG Fc receptor FcγRIIB. This regulated expression of FcγRIIB on FDC and its relation to recall Ab responses were examined both in vitro and in vivo. Trapping of IC in spleen and lymph nodes of FcγRII−/− mice was significantly reduced compared with that in wild-type controls. Addition of ICs to cultures of Ag-specific T and B cells elicited pronounced Ab responses only in the presence of FDCs. However, FDCs derived from FcγRIIB−/− mice supported only low level Ab production in this situation. Similarly, when FcγRIIB−/− mice were transplanted with wild-type Ag-specific T and B cells and challenged with specific Ag, the recall responses were significantly depressed compared with those of controls with wild-type FDC. These results substantiate the hypothesis that FcγRIIB expression on FDCs in GCs is important for FDCs to retain ICs and to mediate the conversion of ICs to a highly immunogenic form and for the generation of strong recall responses.
Regulation of TNF Expression by Multiple Mitogen-Activated Protein Kinase Pathways
Authors: Zhu Wei , Downey Jocelyn S. , Gu Jun , Di Padova Franco , Gram Hermann , Han Jiahuai 
Published: April 2014

AbstractStimulating macrophages with bacterial endotoxin (LPS) activates numerous intracellular signaling pathways that lead to the production of TNF. In this study, we show that four mitogen-activated protein (MAP) kinase pathways are activated in LPS-stimulated macrophages: the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase/stress-activated protein kinase, p38, and Big MAP kinase (BMK)/ERK5 pathways. Although specific activation of a single MAP kinase pathway produces only a modest effect on TNF promoter activation, activation of each MAP kinase pathway is important for full induction of the TNF gene. Interestingly, a dramatic induction of TNF promoter-driven gene expression was observed when all of the four MAP kinase pathways were activated simultaneously, suggesting a cooperative effect among these kinases. Unexpectedly, cis elements known to be targeted by MAP kinases do not play a major role in multiple MAP kinase-induced TNF gene expression. Rather, a 40-bp sequence harboring the TATA box, is responsible for the gene up-regulation induced by MAP kinases. The proximity of the MAP kinase-responsive element to the transcriptional initiation site suggested that MAP kinases regulate the transcriptional initiation complex. Utilizing α-amanitin-resistant RNA polymerase II mutants with or without a C-terminal domain (CTD) deletion, we found that deleting the CTD to 31 tandem repeats (Δ31) led to &gt;90% reduction in MAP kinase-mediated TNF production. Thus, our data demonstrate coordination of multiple MAP kinase pathways in TNF production and suggest that the CTD of RNA polymerase II is required to execute MAP kinase signaling in TNF expression.
Secretory Phospholipase A2-Potentiated Inducible Nitric Oxide Synthase Expression by Macrophages Requires NF-κB Activation
Authors: Baek Suk-Hwan , Kwon Taeg Kyu , Lim Jun-Hee , Lee Yoon-Jeong , Chang Hyeun-Wook , Lee Soo-Jung , Kim Jung-Hye , Kwun Koing-Bo 
Published: April 2014

AbstractThe effect of secretory group II phospholipase A2 (sPLA2) on the expression of the inducible NO synthase (iNOS) and the production of NO by macrophages was investigated. sPLA2 by itself barely stimulated nitrite production and iNOS expression in Raw264.7 cells. However, in combination with LPS, the effects were synergistic. This potentiation was shown for sPLA2 enzymes from sPLA2-transfected stable cells or for purified sPLA2 from human synovial fluid. The effect of PLA2 on iNOS induction appears to be specific for the secretory type of PLA2. LPS-stimulated activation of iNOS was inhibited by the well-known selective inhibitors of sPLA2 such as 12-epi-scalaradial and ρ-bromophenacyl bromide. In contrast, the cytosolic PLA2-specific inhibitors methyl arachidonyl fluorophosphate and arachidonyltrifluoromethyl ketone did not affect LPS-induced nitrite production and iNOS expression. Moreover, when we transfected cDNA-encoding type II sPLA2, we observed that the sPLA2-transfected cells produced two times more nitrites than the empty vector or cytosolic PLA2-transfected cells. The sPLA2-potentiated iNOS expression was associated with the activation of NF-κB. We found that the NF-κB inhibitor pyrrolidinedithiocarbamate prevented nitrite production, iNOS induction, and mRNA accumulation by sPLA2 plus LPS in Raw264.7 cells. Furthermore, EMSA analysis of the activation of the NF-κB involved in iNOS induction demonstrated that pyrrolidinedithiocarbamate prevented the NF-κB binding by sPLA2 plus LPS. Our findings indicated that sPLA2, in the presence of LPS, is a potent activator of macrophages. It stimulates iNOS expression and nitrite production by a mechanism that requires the activation of NF-κB.
Adaptive Immunity and Enhanced CD8+ T Cell Response toListeria monocytogenesin the Absence of Perforin and IFN-γ
Authors: Badovinac Vladimir P. , Harty John T. 
Published: April 2014

AbstractSingle Ag-specific CD8+ T cells from IFN-γ-deficient (GKO) or perforin-deficient (PKO) mice provide substantial immunity against murine infection with Listeria monocytogenes. To address the potential for redundancy between perforin and IFN-γ as CD8+ T cell effector mechanisms, we generated perforin/IFN-γ (PKO/GKO) double-deficient mice. PKO/GKO-derived CD8+ T cells specific for the immunodominant listeriolysin O (LLO91–99) epitope provide immunity to LM infection similar to that provided by Ag-matched wild-type (WT) CD8+ T cells in the liver but reduced in the spleen. Strikingly, polyclonal CD8+ T cells from immunized PKO/GKO mice were ∼100-fold more potent in reducing bacterial numbers than the same number of polyclonal CD8+ T cells from immunized WT mice. This result is probably quantitative, because the frequency of the CD8+ T cell response against the immunodominant LLO91–99 epitope is &gt;4.5-fold higher in PKO/GKO mice than WT mice at 7 days after identical immunizations. Moreover, PKO/GKO mice can be immunized by a single infection with attenuated Listeria to resist &gt;80,000-fold higher challenges with virulent organisms than naive PKO/GKO mice. These data demonstrate that neither perforin nor IFN-γ is required for the development or expression of adaptive immunity to LM. In addition, the results suggest the potential for perforin and IFN-γ to regulate the magnitude of the CD8+ T cell response to infection.
Δ9-Tetrahydrocannabinol Treatment Suppresses Immunity and Early IFN-γ, IL-12, and IL-12 Receptor β2 Responses toLegionella pneumophilaInfection
Authors: Klein Thomas W. , Newton Catherine A. , Nakachi Noryia , Friedman Herman 
Published: April 2014

AbstractThe marijuana cannabinoid, Δ9-tetrahydrocannabinol (THC), suppresses immunity to Legionella pneumophila and development of Th1 activity and cell-mediated immunity. In the current study, THC effects on cytokines regulating the development of Th1 cells were examined. BALB/c mice showed significant increases in serum IL-12 and IFN-γ within hours of infection; however, the levels of these Th1-promoting cytokines as well as resistance to a challenge infection were suppressed by THC (8 mg/kg) injected 18 h before priming. The Th2-promoting cytokine, IL-4, was increased within hours of a Legionella infection and was further increased by THC treatment. These results suggested that THC injection suppressed the cytokine environment promoting Th1 immunity. In additional experiments, THC pretreatment and infection of IL-4 knockout mice showed that serum IL-12 and IFN-γ were suppressed equally in both knockout and normal mice. This suggested that the drug-induced increase in IL-4 was not responsible for the decreases in serum IL-12 and IFN-γ. However, THC treatment was shown to suppress the expression of IL-12 receptor β2 mRNA, indicating that, in addition to suppression of IL-12, THC injection suppressed the expression of IL-12 receptors. Finally, the role of cannabinoid receptors in Th1-promoting cytokine suppression was examined, and results with receptor antagonists showed that both cannabinoid receptors 1 and 2 were involved. It is suggested that suppression of Th1 immunity to Legionella is not due to an increase in IL-4 production but to a decrease in IFN-γ and IL-12. Furthermore, both types of cannabinoid receptors are involved.
NK Cells Cause Liver Injury and Facilitate the Induction of T Cell-Mediated Immunity to a Viral Liver Infection
Authors: Liu Zhang-Xu , Govindarajan Sugantha , Okamoto Shigefumi , Dennert Gunther 
Published: April 2014

AbstractNK cells are a relatively rare cell population in peripheral lymphoid organs but are abundant in the liver, raising questions as to their function in immune responses to infections of this organ. To investigate this, cell-mediated immunity to viral liver infection induced by a type 5, replication-defective, adenovirus was examined. It is shown that NK cells in the absence of T cells cause hepatocyte apoptosis in virus-infected livers associated with an increase in liver enzymes in the serum. Concomitantly, NK cells induce production of IFN-γ, inhibitable by their elimination before infection. NK cells are shown to be necessary for optimal priming of virus-specific T cells, assessed by delayed-type hypersensitivity response and CTL activity, consistent with their ability to secrete IFN-γ. The conclusion is drawn that NK cells mediate two important functions in the liver: they induce cell death in the infected organ and concomitantly stimulate the induction of T cell-mediated immunity by release of IFN-γ.
Resveratrol Suppresses TNF-Induced Activation of Nuclear Transcription Factors NF-κB, Activator Protein-1, and Apoptosis: Potential Role of Reactive Oxygen Intermediates and Lipid Peroxidation
Authors: Manna Sunil K. , Mukhopadhyay Asok , Aggarwal Bharat B. 
Published: April 2014

AbstractResveratrol (trans-3,4′,5-trihydroxystilbene), a polyphenolic phytoalexin found in grapes, fruits, and root extracts of the weed Polygonum cuspidatum, exhibits anti-inflammatory, cell growth-modulatory, and anticarcinogenic effects. How this chemical produces these effects is not known, but it may work by suppressing NF-κB, a nuclear transcription factor that regulates the expression of various genes involved in inflammation, cytoprotection, and carcinogenesis. In this study, we investigated the effect of resveratrol on NF-κB activation induced by various inflammatory agents. Resveratrol blocked TNF-induced activation of NF-κB in a dose- and time-dependent manner. Resveratrol also suppressed TNF-induced phosphorylation and nuclear translocation of the p65 subunit of NF-κB, and NF-κB-dependent reporter gene transcription. Suppression of TNF-induced NF-κB activation by resveratrol was not restricted to myeloid cells (U-937); it was also observed in lymphoid (Jurkat) and epithelial (HeLa and H4) cells. Resveratrol also blocked NF-κB activation induced by PMA, LPS, H2O2, okadaic acid, and ceramide. The suppression of NF-κB coincided with suppression of AP-1. Resveratrol also inhibited the TNF-induced activation of mitogen-activated protein kinase kinase and c-Jun N-terminal kinase and abrogated TNF-induced cytotoxicity and caspase activation. Both reactive oxygen intermediate generation and lipid peroxidation induced by TNF were suppressed by resveratrol. Resveratrol’s anticarcinogenic, anti-inflammatory, and growth-modulatory effects may thus be partially ascribed to the inhibition of activation of NF-κB and AP-1 and the associated kinases.