bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Pulmonary Environment Promotes Th2 Cell Responses After Nasal-Pulmonary Immunization with Antigen Alone, but Th1 Responses Are Induced During Instances of Intense Immune Stimulation
Authors: Jones Harlan P. , Hodge Lisa M. , Fujihashi Kohtaro , Kiyono Hiroshi , McGhee Jerry R. , Simecka Jerry W. 
Published: April 2014

AbstractThe purpose of this study was to determine the nature of the CD4+ Th cell responses induced after nasal-pulmonary immunization, especially those coinciding with previously described pulmonary inflammation associated with the use of the mucosal adjuvant, cholera toxin (CT). The major T cell population in the lungs of naive mice was CD4+, and these cells were shown to be predominantly of Th2 type as in vitro polyclonal stimulation resulted in IL-4, but not IFN-γ, production. After nasal immunization with influenza Ag alone, Th2 cytokine mRNA (IL-4 and IL-5) levels were increased, whereas there was no change in Th1 cytokine (IL-2 and IFN-γ) mRNA expression. The use of the mucosal adjuvant, CT, markedly enhanced pulmonary Th2-type responses; however, there was also a Th1 component to the T cell response. Using in vitro Ag stimulation of pulmonary lymphocytes, influenza virus-specific cytokine production correlated with the mRNA cytokine results. Furthermore, there was a large increase in CD4+ Th cell numbers in lungs after nasal immunization using CT, correlating with the pulmonary inflammatory infiltrate previously described. Coincidentally, both macrophage-inflammatory protein-1α (MIP-1α) and MIP-1β mRNA expression increased in the lungs after immunization with Ag plus CT, while only MIP-1β expression increased when mice were given influenza Ag alone. Our study suggests a mechanism to foster Th1 cell recruitment into the lung, which may impact on pulmonary immune responses. Thus, while Th2 cell responses may be prevalent in modulating mucosal immunity in the lungs, Th1 cell responses contribute to pulmonary defenses during instances of intense immune stimulation.
Immunoendocrine Interactions During Chronic Cysticercosis Determine Male Mouse Feminization: Role of IL-6
Authors: Morales-Montor Jorge , Baig S. , Mitchell R. , Deway K. , Hallal-Calleros C. , Damian R. T. 
Published: April 2014

Abstract
Taenia crassiceps cysticercosis results in an impressive feminization in male mice during chronic infection, characterized by increased serum estradiol levels 100 times their normal values, while those of testosterone and dihydrotestosterone are decreased by 85 and 95% respectively. Concomitantly, the levels of follicle-stimulating hormone and IL-6 are increased 70 and 90 times their normal values in the infected male mice. Since a specific Th1/Th2 shift of the immune response has been previously reported during the chronic infection, and this shift may be associated with the feminization process, we proposed that this shift is induced by immunoendocrine interactions during the disease, and this gives way to a change in the initial resistance to the infection in the male mice, which become as susceptible as female mice. To confirm this hypothesis, we depleted immune system activity in two different ways: total body irradiation and neonatal thymectomy. Our results show that when immune system activity is depleted using either strategy, the male mice do not feminize, and the levels of follicle-stimulating hormone and IL-6 are inhibited. Depletion of IL-6 using IL-6−/− knockout mice does not produce the feminization process stated above, while restitution of the IL-6−/− knockout, irradiated, and thymectomized mice with murine recombinant IL-6 restores the feminization process. Expression of the IL-6 gene was found only in the testes and spleen of infected animals. Our results illustrate the importance of immunoendocrine interactions during a parasitic disease and show a possible new mechanism of parasite establishment in an initially resistant host.
Leishmania amazonensis-Dendritic Cell Interactions In Vitro and the Priming of Parasite-Specific CD4+ T Cells In Vivo
Authors: Qi Hai , Popov Vsevolod , Soong Lynn 
Published: April 2014

Abstract
The progressive disease following Leishmania amazonensis infection in mice requires functional CD4+ T cells, which are primed to a disease-promoting phenotype during the infection. To understand how these pathogenic T cells are generated and the role of dendritic cells (DCs) in this process, we use DCs of susceptible BALB/c and resistant C3H/HeJ mice to examine parasite-DC interactions in vitro as well as the effector phenotype of T cells primed by parasite-exposed DCs in vivo. Our results demonstrate that amastigotes and metacyclics efficiently enter and activate DCs of both genetic backgrounds. Infection with amastigotes fails to induce CD40-depedent IL-12 production, but rather potentiates IL-4 production in BALB/c DCs. Upon transfer into syngeneic recipients, amastigote-exposed BALB/c DCs prime parasite-specific Th cells to produce significantly higher levels of IL-4 and IL-10 than their C3H/HeJ counterparts. Transfer studies with IL-4−/− DCs indicate that this enhanced Th2 priming seen in BALB/c mice is partially due to the IL-4 production by amastigote-carrying DCs. These results suggest that L. amazonensis amastigotes may condition DCs of a susceptible host to a state that favors activation of pathogenic CD4+ T cells, and thereby provide a new perspective on the pathogenesis of cutaneous leishmaniasis and protozoan parasite-host interactions in general.
Quantifying the Relationship Between Multiple Immunological Parameters and Host Resistance: Probing the Limits of Reductionism
Authors: Keil Deborah , Luebke Robert W. , Pruett Stephen B. 
Published: April 2014

Abstract
Although reductionist experimental designs are excellent for identifying cells, molecules, or functions involved in resistance to particular microbes or cancer cells, they do not provide an integrated, quantitative view of immune function. In the present study, mice were treated with either dexamethasone (DEX) or cyclosporin A (CyA), and immune function and host resistance were evaluated. Multivariate statistical methods were used to describe the relative importance of a broad range of immunological parameters for host resistance in mice treated with various dosages of DEX. Multiple regression and logistic regression analysis indicated that changes in 24 immunological parameters explained a substantial portion of the changes in resistance to B16F10 tumor cells or streptococcus group B. However, at least 40% of the change in host resistance remained unexplained. DEX at all dosages substantially suppressed numerous relevant immunological parameters, but significantly decreased resistance to Listeria monocytogenes only at the highest dosage. In contrast, CyA substantially decreased resistance to L. monocytogenes at dosages that caused relatively minor suppression of just a few immunological parameters (unfortunately, CyA data and host resistance data for L. monocytogenes were not suitable for multivariate analysis). These results illustrate that mathematical models can be used to explain changes in host resistance on the basis of changes in immune parameters, and that moderate changes in relevant immunological parameters may not produce the types of changes in host resistance expected on the basis of results from reductionist experimental designs.
Phosphatidylinositol 3-Kinase Confers Resistance to Encephalomyocarditis and Herpes Simplex Virus-Induced Cell Death Through the Activation of Distinct Downstream Effectors
Authors: Prejean Christine , Sarma Tulika , Kurnasov Oleg , Usacheva Anna , Hemmings Brian , Cantley Lewis , Fruman David A. , Morrison Lynda A. , Buller R. Mark , Colamonici Oscar R. 
Published: April 2014

Abstract
The Janus kinase/STAT pathway has emerged as the paradigm of IFN-induced protection from viral infections. However, the possible participation of other signaling proteins in this protection is not clearly understood. In this report, we demonstrate that activation of phosphatidylinositol 3-kinase (PI3K) by either serum factors or IFNs blocks cell death induced by encephalomyocarditis virus (EMCV) and HSV. This increased resistance to virus-induced cell death does not involve the activation of the STAT pathway and occurs in the presence of normal viral replication. Interestingly, the cell uses two different PI3K regulated pathways to block EMCV- and HSV-induced cell death. The increased sensitivity of p85α−/− embryonic fibroblasts to EMCV-induced cell death is specifically corrected by overexpression of an activated allele of Akt/protein kinase B, but not activated mitogen-activated protein kinase extracellular kinase. Conversely, the augmented sensitivity of p85α−/− cells to HSV-induced cell death was compensated for by expression of an activated form of mitogen-activated protein kinase extracellular kinase, but not by activated Akt/protein kinase B. We conclude from these data that PI3K-activated pathways function in parallel with the Janus kinase/STAT pathway to protect cells from the lethal effects of viruses.
A Dual-Function DNA Vaccine Encoding Carcinoembryonic Antigen and CD40 Ligand Trimer Induces T Cell-Mediated Protective Immunity Against Colon Cancer in Carcinoembryonic Antigen-Transgenic Mice
Authors: Xiang Rong , Primus F. James , Ruehlmann J. Michael , Niethammer Andreas G. , Silletti Steve , Lode Holger N. , Dolman Carrie S. , Gillies Stephen D. , Reisfeld Ralph A. 
Published: April 2014

Abstract
A carcinoembryonic Ag (CEA)-based DNA vaccine encoding both CEA and CD40 ligand trimer achieved effective tumor-protective immunity against murine colon carcinoma in CEA-transgenic mice by activating both naive T cells and dendritic cells. Peripheral T cell tolerance to CEA was broken in a prophylactic model by this novel, dual-function DNA vaccine, whose efficacy was further enhanced by boosts with a recombinant Ab-IL-2 fusion protein (huKS1/4-IL-2). These conclusions are supported by four lines of evidence. First, a lethal challenge of MC38-CEA-KS Ag murine colon carcinoma cells was for the first time completely rejected in 100% of experimental animals treated by oral gavage of this DNA vaccine carried by attenuated Salmonella typhimurium, followed by five boosts with huKS1/4-IL-2. Second, specific activation of dendritic cells was indicated by their marked up-regulation in expression of costimulatory molecules B7.1 (CD80), B7.2 (CD86), and ICAM-1. Third, a decisive increase over control values was observed in both MHC class I Ag-restricted cytotoxicity of CTLs from successfully vaccinated mice and secretion of proinflammatory cytokines IFN-γ and IL-12. Fourth, activation of CTLs was augmented, as indicated by up-regulation of activity markers LFA-1, CD25, CD28, and CD69. Taken together, these results suggest that a dual-function DNA vaccine encoding CEA and CD40 ligand trimer combined with tumor-targeted IL-2 may be a promising strategy for the rational development of DNA-based cancer vaccines for future clinical applications.
Distinct CD8 T Cell Functions Mediate Susceptibility to Histoplasmosis During Chronic Viral Infection
Authors: Wu-Hsieh Betty A. , Whitmire Jason K. , de Fries Rici , Lin Jr-Shiuan , Matloubian Mehrdad , Ahmed Rafi 
Published: April 2014

Abstract
It has long been recognized that some viral infections result in generalized immune suppression. In acute infections, this period of suppressed immunity is relatively short. However, chronic infections associated with a prolonged period of immune suppression present far greater risks. Here, we examined the role of CD8 T cell responses following viral infection in immunity to systemic histoplasmosis. Although wild-type mice with systemic histoplasmosis were able to control the infection, those simultaneously infected with lymphocytic choriomeningitis virus clone 13 showed reduced immunity with greater fungal burden and high mortality. The immune suppression was associated with loss of CD4 T cells and B cells, generalized splenic atrophy, and inability to mount a granulomatous response. Removing the anti-viral CD8 T cells in the coinfected mice enabled them to reduce the fungal burden and survive the infection. Their lymphoid organs were replenished with CD4 T and B cells. In contrast to wild-type mice, perforin-deficient mice infected with lymphocytic choriomeningitis virus clone 13 and Histoplasma showed an absence of immunopathology, but the animals still died. These results show that CD8 T cells can suppress immunity through different mechanisms; although immunopathology is perforin-dependent, lethality is perforin-independent.
Acute Toxoplasmosis Leads to Lethal Overproduction of Th1 Cytokines
Authors: Mordue Dana G. , Monroy Fernando , La Regina Marie , Dinarello Charles A. , Sibley L. David 
Published: April 2014

AbstractVirulence in Toxoplasma gondii is strongly influenced by the genotype of the parasite. Type I strains uniformly cause rapid death in mice regardless of the host genotype or the challenge dose. In contrast, the outcome of infections with type II strains is highly dependent on the challenge dose and the genotype of the host. To understand the basis of acute virulence in toxoplasmosis, we compared low and high doses of the RH strain (type I) and the ME49/PTG strain (type II) of T. gondii in outbred mice. Differences in virulence were reflected in only modestly different growth rates in vivo, and both strains disseminated widely to different tissues. The key difference in the virulent RH strain was the ability to reach high tissue burdens rapidly following a low dose challenge. Lethal infections caused by type I (RH) or type II (PTG) strain infections were accompanied by extremely elevated levels of Th1 cytokines in the serum, including IFN-γ, TNF-α, IL-12, and IL-18. Extensive liver damage and lymphoid degeneration accompanied the elevated levels of cytokines produced during lethal infection. Increased time of survival following lethal infection with the RH strain was provided by neutralization of IL-18, but not TNF-α or IFN-γ. Nonlethal infections with a low dose of type II PTG strain parasites were characterized by a modest induction of Th1 cytokines that led to control of infection and minimal damage to host tissues. Our findings establish that overstimulation of immune responses that are normally necessary for protection is an important feature of acute toxoplasmosis.
Lack of CCR2 Results in Increased Mortality and Impaired Leukocyte Activation and Trafficking Following Infection of the Central Nervous System with a Neurotropic Coronavirus
Authors: Chen Benjamin P. , Kuziel William A. , Lane Thomas E. 
Published: April 2014

Abstract
In the present study, we evaluated the role of CCR2 in a model of viral-induced neurologic disease. An orchestrated expression of chemokines, including the CCR2 ligands monocyte chemoattractant protein-1/CCL2 and monocyte chemoattractant protein-3/CCL7, occurs within the CNS following infection with mouse hepatitis virus (MHV). Infection of mice lacking CCR2 (CCR2−/−) with MHV resulted in increased mortality and enhanced viral recovery from the brain that correlated with reduced (p ≤ 0.04) T cell and macrophage/microglial (determined by F4/80 Ag expression, p ≤ 0.004) infiltration into the CNS. Moreover, MHV-infected CCR2−/− mice displayed a significant decrease in Th1-associated factors IFN-γ (p ≤ 0.001) and RANTES/CCL5 (p ≤ 0.002) within the CNS as compared with CCR2+/+ mice. Further, peripheral CD4+ and CD8+ T cells from immunized CCR2−/− mice displayed a marked reduction in IFN-γ production in response to viral Ag and did not migrate into the CNS of MHV-infected recombination-activating gene (RAG)1−/− mice following adoptive transfer. In addition, macrophage/microglial infiltration into the CNS of RAG1−/− mice receiving CCR2−/− splenocytes was reduced (p ≤ 0.05), which correlated with a reduction in the severity of demyelination (p ≤ 0.001) as compared with RAG1−/− mice receiving splenocytes from CCR2+/+ mice. Collectively, these results indicate an important role for CCR2 in host defense and disease by regulating leukocyte activation and trafficking.
High-Dose Leptin Activates Human Leukocytes Via Receptor Expression on Monocytes
Authors: Zarkesh-Esfahani Hamid , Pockley Graham , Metcalfe Russell A. , Bidlingmaier Martin , Wu Zida , Ajami Abolghasem , Weetman Anthony P. , Strasburger Christian J. , Ross Richard J. M. 
Published: April 2014

Abstract
Leptin is capable of modulating the immune response. Proinflammatory cytokines induce leptin production, and we now demonstrate that leptin can directly activate the inflammatory response. RNA expression for the leptin receptor (Ob-R) was detectable in human PBMCs. Ob-R expression was examined at the protein level by whole blood flow cytometry using an anti-human Ob-R mAb 9F8. The percentage of cells expressing leptin receptor was 25 ± 5% for monocytes, 12 ± 4% for neutrophils, and 5 ± 1% for lymphocytes (only B lymphocytes). Incubation of resting PBMCs with leptin induced rapid expression of TNF-α and IL-6 mRNA and a dose-dependent production of TNF-α and IL-6 by monocytes. Incubation of resting PBMCs with high-dose leptin (250 ng/ml, 3–5 days) induced proliferation of resting cultured PBMCs and their secretion of TNF-α (5-fold), IL-6 (19-fold), and IFN-γ (2.5-fold), but had no effect on IL-4 secretion. The effect of leptin was distinct from, and additive to, that seen after exposure to endotoxin or activation by the mixed lymphocyte reaction. In conclusion, Ob-R is expressed on human circulating leukocytes, predominantly on monocytes. At high doses, leptin induces proinflammatory cytokine production by resting human PBMCs and augments the release of these cytokines from activated PBMCs in a pattern compatible with the induction of Th1 cytokines. These results demonstrate that leptin has a direct effect on the generation of an inflammatory response. This is of relevance when considering leptin therapy and may partly explain the relationship among leptin, proinflammatory cytokines, insulin resistance, and obesity.
Induction of Hypoxia-Inducible Factor-1α and Activation of Caspase-3 in Hypoxia-Reoxygenated Bone Marrow Stroma Is Negatively Regulated by the Delayed Production of Substance P
Authors: Qian Jing , Ramroop Kavita , McLeod Alnela , Bandari Persis , Livingston David H. , Harrison Jonathan S. , Rameshwar Pranela 
Published: April 2014

Abstract
The bone marrow (BM), which is the major site of immune cell development in the adult, responds to different stimuli such as inflammation and hemorrhagic shock. Substance P (SP) is the major peptide encoded by the immune/hemopoietic modulator gene, preprotachykinin-1 (PPT-I). Differential gene expression using a microarray showed that SP reduced hypoxia-inducible factor-1α (HIF-1α) mRNA levels in BM stroma. Because long-term hypoxia induced the expression of PPT-I in BM mononuclear cells, we used timeline studies to determine whether PPT-I is central to the biologic responses of BM stroma subjected to 30-min hypoxia (pO2 = 35 mm Hg) followed by reoxygenation. HIF-1α mRNA and protein levels were increased up to 12 h. At this time, β-PPT-I mRNA was detected with the release of SP at 16 h. SP release correlated with down-regulation of HIF-1α to baseline. A direct role for SP in HIF-1α expression was demonstrated as follows: 1) transient knockout of β-PPT-I showed an increase in HIF-1α expression up to 48 h of reoxygenation; and 2) HIF-1α expression remained baseline during reoxygenation when stroma was subjected to hypoxia in the presence of SP. Reoxygenation activated the PPT-I promoter with concomitant nuclear translocation of HIF-1α that can bind to the respective consensus sequences within the PPT-I promoter. SP reversed active caspase-3, an indicator of apoptosis and erythropoiesis, to homeostasis level after reoxygenation of hypoxic stroma. The results show that during reoxgenation the PPT-I gene acts as a negative regulator on the expression of HIF-1α and active caspase-3 in BM stroma subjected to reoxygenation.
The Functional Role of Rho and Rho-Associated Coiled-Coil Forming Protein Kinase in Eotaxin Signaling of Eosinophils
Authors: Adachi Tetsuya , Vita Randi , Sannohe Satoshi , Stafford Susan , Alam Rafeul , Kayaba Hiroyuki , Chihara Junichi 
Published: April 2014

AbstractThe CC chemokine eotaxin plays a pivotal role in local accumulation of eosinophils. Very little is known about the eotaxin signaling in eosinophils except the activation of the mitogen-activated protein (MAP) kinase family. The p21 G protein Rho and its substrate Rho-associated coiled-coil forming protein kinase (ROCK) regulate the formation of stress fibers and focal adhesions. In the present study, we studied the functional relevance of Rho and ROCK in eosinophils using the ROCK inhibitor (Y-27632) and exoenzyme C3, a specific Rho inhibitor. Eotaxin stimulates activation of Rho A and ROCK II in eosinophils. Exoenzyme C3 almost completely inhibited the ROCK activity, indicating that ROCK is downstream of Rho. We then examined the role of Rho and ROCK in eosinophil chemotaxis. The eotaxin-induced eosinophil chemotaxis was significantly inhibited by exoenzyme C3 or Y-27632. Because extracellular signal-regulated kinase (ERK)1/2 and p38 MAP kinases are activated by eotaxin and are critical for eosinophil chemotaxis, we investigated whether Rho and ROCK are upstream of these MAP kinases. C3 partially inhibited eotaxin-induced phosphorylation of ERK1/2 but not p38. In contrast, neither ERK1/2 nor p38 phosphorylation was abrogated by Y-27632. Both C3 and Y-27632 reduced reactive oxygen species production from eosinophils. We conclude that both Rho and ROCK are important for eosinophil chemotaxis and reactive oxygen species production. There is a dichotomy of downstream signaling pathways of Rho, namely, Rho-ROCK and Rho-ERK pathways. Taken together, eosinophil chemotaxis is regulated by multiple signaling pathways that involve at least ROCK, ERK, and p38 MAP kinase.
Intracisternally Localized Bacterial DNA Containing CpG Motifs Induces Meningitis
Authors: Deng Guo-Min , Liu Zai-Qing , Tarkowski Andrej 
Published: April 2014

Abstract
Unmethylated CpG motifs are frequently found in bacterial DNA, and have recently been shown to exert immunostimulatory effects on leukocytes. Since bacterial infections in the CNS will lead to local release of prokaryotic DNA, we wanted to investigate whether such an event might trigger meningitis. To that end, we have intracisternally injected mice and rats with bacterial DNA and oligonucleotides containing CpG motifs. Histopathological signs of meningitis were evident within 12 h and lasted for at least 14 days, and were characterized by an influx of monocytic, Mac-3+ cells and by a lack of T lymphocytes. To study the mechanisms whereby unmethylated CpG DNA gives rise to meningitis, we deleted the monocyte/macrophage population leading to abrogation of brain inflammation. Also, interaction with NF-κB using antisense technology led to down-regulation of proinflammatory cytokine production and frequency of meningitis. Furthermore, specific interactions with vascular selectin expression and inhibition of NO synthase led to a significant amelioration of meningitis, altogether indicating that this condition is dependent on macrophages and their products. In contrast, neutrophils, NK cells, T/B lymphocytes, IL-12, and complement system were not instrumental in meningitis triggered by bacterial DNA containing CpG motifs. This study proves that bacterial DNA containing unmethylated CpG motifs induces meningitis, and indicates that this condition is mediated in vivo by activated macrophages.