bluuebunny/crossref_metadata_2025_split huggingface dataset:
β-Catenin Regulates Positive Selection of Thymocytes but Not Lineage Commitment
Authors: Yu Qing , Sen Jyoti Misra 
Published: April 2014

Abstract
Positive selection and lineage commitment to the cytolytic or helper lineage of T cells result in coordinated expression of MHC class I-restricted TCR and CD8 coreceptor or MHC class II-restricted TCR and CD4 molecule. Positive selection signals also regulate the survival and generation of requisite numbers of cytolytic or Th cells. β-Catenin is the major transcriptional cofactor of T cell factor and plays a role in thymocyte development. In this study, using mice expressing stabilized β-catenin and mice with T cell-specific deletion of β-catenin, we show that β-catenin regulates positive selection, but not lineage commitment of thymocytes. Furthermore, β-catenin expression accelerates the timing of mature CD8 thymocyte generation such that CD4 and CD8 single-positive thymocytes mature with the same kinetics during development.
Description and Mapping of the Resistance of DBA/2 Mice to TNF-Induced Lethal Shock
Authors: Wielockx Ben , Staelens Jan , Puimège Leen , Vanlaere Ineke , Van Roy Maarten , van Lint Philippe , Van Roy Frans , Libert Claude 
Published: April 2014

Abstract
In our search for genes that inhibit the inflammatory effects of TNF without diminishing its antitumor capacities we found that, compared with C57BL/6 mice, DBA/2 mice exhibit a dominant resistance to TNF-induced lethality. Tumor-bearing (C57BL/6 × DBA/2)(BXD)F1 mice completely survived an otherwise lethal TNF/IFN-γ-antitumor therapy with complete regression of the tumor. This was not the case for C57BL/6 mice. Genetic linkage analysis revealed that TNF resistance is linked to a major locus on distal chromosome 6 and a minor locus on chromosome 17. Compared with littermate controls, chromosome substitution mice carrying a DBA/2 chromosome 6 in a C57BL/6 background were significantly protected against TNF and TNF/IFN-γ, albeit less so than DBA/2 mice. Definition of a critical region of 13 Mb on chromosome 6 was the highest mapping resolution obtained. Further analysis of candidate genes may provide a powerful tool to control TNF-induced pathologies in humans.
Increasing the Recruitment of Neutrophils to the Site of Infection Dramatically Attenuates Borrelia burgdorferi Infectivity
Authors: Xu Qilong , Seemanapalli Sunita V. , Reif Kathryn E. , Brown Charles R. , Liang Fang Ting 
Published: April 2014

Abstract
Borrelia burgdorferi infection causes an initial skin lesion called erythema migrans (EM) in human Lyme disease and in models of monkey and rabbit borreliosis. EM results from the inflammatory response triggered by spirochete replication and likely develops to contain the initial infection but allows bacterial dissemination to occur. The essential lack of neutrophil involvement in EM histopathology prompted us to examine the consequence of increasing their recruitment in the inflammatory response to the Lyme disease agent. B. burgdorferi was modified genetically to constitutively express and secrete the chemokine KC, a neutrophil chemoattractant. After inoculation into the dermis of the murine host, control spirochetes induced an infiltration of macrophages, neutrophils, and basophils within 6 h; however, the recruited neutrophils and basophils were quickly substituted by eosinophils, and the inflammatory response became macrophage dominant by 16 h. Such a response failed to contain the initial infection and allowed the spirochetes to disseminate. In contrast, B. burgdorferi with KC secretion induced an intensive neutrophil infiltration at the inoculation site, and as a result, the host’s ability to control the initial infection was greatly enhanced. Taken together, this study suggests that the failure of sufficient neutrophil recruitment and activation during the initial inflammatory response may allow B. burgdorferi to effectively colonize the mammalian host.
Thiocyanate Transport in Resting and IL-4-Stimulated Human Bronchial Epithelial Cells: Role of Pendrin and Anion Channels
Authors: Pedemonte Nicoletta , Caci Emanuela , Sondo Elvira , Caputo Antonella , Rhoden Kerry , Pfeffer Ulrich , Di Candia Michele , Bandettini Roberto , Ravazzolo Roberto , Zegarra-Moran Olga , Galietta Luis J. V. 
Published: April 2014

Abstract
SCN− (thiocyanate) is an important physiological anion involved in innate defense of mucosal surfaces. SCN− is oxidized by H2O2, a reaction catalyzed by lactoperoxidase, to produce OSCN− (hypothiocyanite), a molecule with antimicrobial activity. Given the importance of the availability of SCN− in the airway surface fluid, we studied transepithelial SCN− transport in the human bronchial epithelium. We found evidence for at least three mechanisms for basolateral to apical SCN− flux. cAMP and Ca2+ regulatory pathways controlled SCN− transport through cystic fibrosis transmembrane conductance regulator and Ca2+-activated Cl− channels, respectively, the latter mechanism being significantly increased by treatment with IL-4. Stimulation with IL-4 also induced the strong up-regulation of an electroneutral SCN−/Cl− exchange. Global gene expression analysis with microarrays and functional studies indicated pendrin (SLC26A4) as the protein responsible for this SCN− transport. Measurements of H2O2 production at the apical surface of bronchial cells indicated that the extent of SCN− transport is important to modulate the conversion of this oxidant molecule by the lactoperoxidase system. Our studies indicate that the human bronchial epithelium expresses various SCN− transport mechanisms under resting and stimulated conditions. Defects in SCN− transport in the airways may be responsible for susceptibility to infections and/or decreased ability to scavenge oxidants.
Toxoplasma gondii Dysregulates IFN-γ-Inducible Gene Expression in Human Fibroblasts: Insights from a Genome-Wide Transcriptional Profiling
Authors: Kim Seon-Kyeong , Fouts Ashley E. , Boothroyd John C. 
Published: April 2014

Abstract
Toxoplasma gondii is an obligate intracellular parasite that persists for the life of a mammalian host. The parasite’s ability to block the potent IFN-γ response may be one of the key mechanisms that allow Toxoplasma to persist. Using a genome-wide microarray analysis, we show here a complete dysregulation of IFN-γ-inducible gene expression in human fibroblasts infected with Toxoplasma. Notably, 46 of the 127 IFN-γ-responsive genes were induced and 19 were suppressed in infected cells before they were exposed to IFN-γ, indicating that other stimuli produced during infection may also regulate these genes. Following IFN-γ treatment, none of the 127 IFN-γ-responsive genes could be significantly induced in infected cells. Immunofluorescence assays showed at single-cell levels that infected cells, regardless of which Toxoplasma strain was used, could not be activated by IFN-γ to up-regulate the expression of IFN regulatory factor 1, a transcription factor that is under the direct control of STAT1, whereas uninfected cells in the same culture expressed IFN regulatory factor 1 normally in response to IFN-γ. STAT1 trafficked to the nucleus normally and indistinguishably in all uninfected and infected cells treated with IFN-γ, indicating that the inhibitory effects of Toxoplasma infection likely occur via blocking STAT1 transcriptional activity in the nucleus. In contrast, a closely related apicomplexan, Neospora caninum, was unable to inhibit IFN-γ-induced gene expression. A differential ability to interfere with the IFN-γ response may, in part, account for the differences in the pathogenesis seen among Toxoplasma and Neospora parasite strains.
Mold Allergen, Pen c 13, Induces IL-8 Expression in Human Airway Epithelial Cells by Activating Protease-Activated Receptor 1 and 2
Authors: Chiu Li-Li , Perng Diahn-Warng , Yu Chia-Hsien , Su Song-Nan , Chow Lu-Ping 
Published: April 2014

Abstract
Allergenic serine proteases are important in the pathogenesis of asthma. One of these, Pen c 13, is the immunodominant allergen produced by Penicillium citrinum. Many serine proteases induce cytokine expression, but whether Pen c 13 does so in human respiratory epithelial cells is not known. In this study, we investigated whether Pen c 13 caused IL-8 release and activated protease-activated receptors (PARs) in airway epithelial cells. In airway-derived A549 cells and normal human airway epithelial cells, Pen c 13 induced IL-8 release in a dose-dependent manner. Pen c 13 also increased IL-8 release in a time-dependent manner in A549 cells. Pen c 13 cleaved PAR-1 and PAR-2 at their activation sites. Treatment with Pen c 13 induced intracellular Ca2+ mobilization and desensitized the cells to the action of other proteases and PAR-1 and PAR-2 agonists. Moreover, Pen c 13-mediated IL-8 release was significantly decreased in Ca2+-free medium and was abolished by the protease inhibitors, PMSF and 4-(2-aminoethyl) benzenesulfonyl fluoride. Blocking Abs against the cleavage sites of PAR-1 and PAR-2, but not of PAR-4, inhibited Pen c 13-induced IL-8 production, as did inhibition of phospholipase C. Pen c 13 induced IL-8 expression via activation of ERK 1/2, and not of p38 and JNK. In addition, treatment of A549 cells or normal human airway epithelial cells with Pen c 13 increased phosphorylation of ERK 1/2 by a Ca2+-dependent pathway. These finding show that Pen c 13 induces IL-8 release in airway epithelial cells and that this is dependent on PAR-1 and PAR-2 activation and intracellular calcium.
Inhibition of CCL1-CCR8 Interaction Prevents Aggregation of Macrophages and Development of Peritoneal Adhesions
Authors: Hoshino Akiyoshi , Kawamura Yuki I. , Yasuhara Masato , Toyama-Sorimachi Noriko , Yamamoto Kenji , Matsukawa Akihiro , Lira Sergio A. , Dohi Taeko 
Published: April 2014

Abstract
Peritoneal adhesions are a significant complication of surgery and visceral inflammation; however, the mechanism has not been fully elucidated. The aim of this study was to clarify the mechanism of peritoneal adhesions by focusing on the cell trafficking and immune system in the peritoneal cavity. We investigated the specific recruitment of peritoneal macrophages (PMφ) and their expression of chemokine receptors in murine models of postoperative and postinflammatory peritoneal adhesions. PMφ aggregated at the site of injured peritoneum in these murine models of peritoneal adhesions. The chemokine receptor CCR8 was up-regulated in the aggregating PMφ when compared with naive PMφ. The up-regulation of CCR8 was also observed in PMφ, but not in bone marrow-derived Mφ, treated with inflammatory stimulants including bacterial components and cytokines. Importantly, CCL1, the ligand for CCR8, a product of both PMφ and peritoneal mesothelial cells (PMCs) following inflammatory stimulation, was a potent enhancer of CCR8 expression. Cell aggregation involving PMφ and PMCs was induced in vitro in the presence of CCL1. CCL1 also up-regulated mRNA levels of plasminogen activator inhibitor-1 in both PMφ and PMCs. CCR8 gene-deficient mice or mice treated with anti-CCL1-neutralizing Ab exhibited significantly reduced postoperational peritoneal adhesion. Our study now establishes a unique autocrine activation system in PMφ and the mechanism for recruitment of PMφ together with PMCs via CCL1/CCR8, as immune responses of peritoneal cavity, which triggers peritoneal adhesions.
Coexposure to Environmental Tobacco Smoke Increases Levels of Allergen-Induced Airway Remodeling in Mice
Authors: Min Myung Goo , Song Dae Jin , Miller Marina , Cho Jae Youn , McElwain Shauna , Ferguson Paul , Broide David H. 
Published: April 2014

Abstract
Environmental tobacco smoke (ETS) can increase asthma symptoms and the frequency of asthma attacks. However, the contribution of ETS to airway remodeling in asthma is at present unknown. In this study, we have used a mouse model of allergen-induced airway remodeling to determine whether the combination of chronic exposure to ETS and chronic exposure to OVA allergen induces greater levels of airway remodeling than exposure to either chronic ETS or chronic OVA allergen alone. Mice exposed to chronic ETS alone did not develop significant eosinophilic airway inflammation, airway remodeling, or increased airway hyperreactivity to methacholine. In contrast, mice exposed to chronic OVA allergen had significantly increased levels of peribronchial fibrosis, increased thickening of the smooth muscle layer, increased mucus, and increased airway hyperreactivity which was significantly enhanced by coexposure to the combination of chronic ETS and chronic OVA allergen. Mice coexposed to chronic ETS and chronic OVA allergen had significantly increased levels of eotaxin-1 expression in airway epithelium which was associated with increased numbers of peribronchial eosinophils, as well as increased numbers of peribronchial cells expressing TGF-β1. These studies suggest that chronic coexposure to ETS significantly increases levels of allergen-induced airway remodeling (in particular smooth muscle thickness) and airway responsiveness by up-regulating expression of chemokines such as eotaxin-1 in airway epithelium with resultant recruitment of cells expressing TGF-β1 to the airway and enhanced airway remodeling.
Inhibition of Transmethylation Down-Regulates CD4 T Cell Activation and Curtails Development of Autoimmunity in a Model System
Authors: Lawson Brian R. , Manenkova Yulia , Ahamed Jasimuddin , Chen Xiaoru , Zou Jian-Ping , Baccala Roberto , Theofilopoulos Argyrios N. , Yuan Chong 
Published: April 2014

Abstract
Transmethylation affects several cellular events, including T cell activation, and blockade of this pathway may curtail inflammatory/autoimmune responses. Here, we demonstrate that transmethylation inhibition by a novel reversible S-adenosyl-l-homocysteine hydrolase inhibitor leads to immunosuppression by reducing phosphorylation of several key proteins involved in TCR signaling, including Akt, Erk1/2, and NF-κB. Remarkably, this effect was largely restricted to CD4 T cells and correlated with reduced arginine methylation of Vav1, an essential guanine nucleotide exchange factor in T cell stimulation. Treatment with the transmethylation inhibitor averted, and even ameliorated, the CD4-mediated autoimmune disease, experimental autoimmune encephalomyelitis. The data suggest that transmethylation is required for CD4 T cell activation, and its inhibition may be a novel approach in the treatment of multiple sclerosis, and other CD4-mediated autoimmune diseases.
Circulating Immune Complexes (IC) and IC-Induced Levels of GM-CSF Are Increased in Sudanese Patients with Acute Visceral Leishmania donovani Infection Undergoing Sodium Stibogluconate Treatment: Implications for Disease Pathogenesis
Authors: Elshafie Amir Ibrahim , Åhlin Erik , Mathsson Linda , ElGhazali Gehad , Rönnelid Johan 
Published: April 2014

Abstract
Infection with Leishmania donovani is associated with IL-10 as well as with GM-CSF. Immune complexes (IC) exert important functions by stimulation of monocytes/macrophage-mediated production of pro- and anti-inflammatory cytokines in rheumatic diseases. In this investigation, we have explored IC-induced cytokine production during Leishmania infection. Sera from 43 patients with visceral leishmaniasis (VL), 17 patients with post-kala-azar dermal leishmaniasis, and 20 healthy Sudanese controls were precipitated with polyethylene glycol (PEG). The PEG precipitates were added to serum-free PBMC for 20 h,whereupon supernatant levels of IL-1β, IL-6, IL-10, IL-1 receptor antagonist protein, TNF-α, TNF receptor p75, and GM-CSF were investigated using ELISA. Circulating levels of C1q-binding IC were also measured in the serum samples. PEG precipitates from Leishmania-infected patients induced significantly higher levels of GM-CSF (p = 0.0037) and IL-10 (p &lt; 0.0001), as well as of IL-6 (p &lt; 0.0001) and IL-1 receptor antagonist (p = 0.0238) as compared with PEG precipitates from controls. Patients with acute VL as well as VL patients receiving sodium stibogluconate treatment displayed significantly increased levels of PEG precipitate-induced GM-CSF. The induction of GM-CSF by circulating IC was especially prominent in acute VL patients receiving sodium stibogluconate treatment; ANOVA revealed significant interaction between disease activity and treatment for PEG precipitate-induced levels of GM-CSF (disease activity, p = 0.0006; treatment, p = 0.0005; interaction, p = 0.0046). Parallel associations were determined for C1q-binding immune complexes, but not for any cytokine other than GM-CSF. The importance of IC-induced GM-CSF in leishmaniasis warrants further study.
Krüppel-Like Transcription Factor 13 Regulates T Lymphocyte Survival In Vivo
Authors: Zhou Meixia , McPherson Lisa , Feng Dongdong , Song An , Dong Chen , Lyu Shu-Chen , Zhou Lu , Shi Xiaoyan , Ahn Yong-Tae , Wang Demin , Clayberger Carol , Krensky Alan M. 
Published: April 2014

Abstract
Krüppel-like transcription factor (KLF)13, previously shown to regulate RANTES expression in vitro, is a member of the Krüppel- like family of transcription factors that controls many growth and developmental processes. To ascertain the function of KLF13 in vivo, Klf13-deficient mice were generated by gene targeting. As expected, activated T lymphocytes from Klf13−/− mice show decreased RANTES expression. However, these mice also exhibit enlarged thymi and spleens. TUNEL, as well as spontaneous and activation-induced death assays, demonstrated that prolonged survival of Klf13−/− thymocytes was due to decreased apoptosis. Microarray analysis suggests that protection from apoptosis-inducing stimuli in Klf13−/− thymocytes is due in part to increased expression of BCL-XL, a potent antiapoptotic factor. This finding was confirmed in splenocytes and total thymocytes by real-time quantitative PCR and Western blot as well as in CD4+CD8− single-positive thymocytes by real-time quantitative PCR. Furthermore, EMSA and luciferase reporter assays demonstrated that KLF13 binds to multiple sites within the Bcl-XL promoter and results in decreased Bcl-XL promoter activity, making KLF13 a negative regulator of BCL-XL.
Protein Inhibitor of Activated STAT 3 Modulates Osteoclastogenesis by Down-Regulation of NFATc1 and Osteoclast-Associated Receptor
Authors: Kim Kabsun , Lee Junwon , Kim Jung Ha , Jin Hye Mi , Zhou Bin , Lee Soo Young , Kim Nacksung 
Published: April 2014

Abstract
Protein inhibitor of activated STAT3 (PIAS3) has been shown to regulate the activity of various transcription factors. In this study, we show that the overexpression of PIAS3 in bone marrow-derived monocyte/macrophage lineage cells attenuates osteoclast formation and down-regulates the expression of NFATc1 and osteoclast-associated receptor (OSCAR), which are important modulators in osteoclastogenesis. PIAS3 has been shown to associate with histone deacetylase 1 as well as with transcription factors, including the microphthalmia transcription factor, NFATc1, and c-Fos. Moreover, overexpression of PIAS3 inhibits the transactivation of target genes such as NFATc1 and OSCAR. This inhibitory effect of PIAS3 is possibly mediated by histone deacetylase 1 recruitment to the promoter regions of NFATc1 and OSCAR. Furthermore, silencing of PIAS3 by RNA interference in osteoclast precursors enhances osteoclast formation as well as gene expression of NFATc1 and OSCAR. Taken together, our results reveal that PIAS3 acts as a modulator in osteoclastogenesis.
Divergent Effects of BAFF on Human Memory B Cell Differentiation into Ig-Secreting Cells
Authors: Darce Jaime R. , Arendt Bonnie K. , Chang Sook Kyung , Jelinek Diane F. 
Published: April 2014

Abstract
B cell-activating factor belonging to the TNF family (BAFF) plays a critical role in B cell maturation, yet its precise role in B cell differentiation into Ig-secreting cells (ISCs) remains unclear. In this study, we find that upon isolation human naive and memory B (MB) cells have prebound BAFF on their surface, whereas germinal center (GC) B cells lack detectable levels of prebound BAFF. We attribute their lack of prebound BAFF to cell activation, because we demonstrate that stimulation of naive and MB cells results in the loss of prebound BAFF. Furthermore, the absence of prebound BAFF on GC B cells is not related to a lack of BAFF-binding receptors or an inability to bind exogenous BAFF. Instead, our data suggest that accessibility to soluble BAFF is limited within GCs, perhaps to prevent skewing of the conventional B cell differentiation program. In support of this concept, whereas BAFF significantly enhances ISC differentiation in response to T cell-dependent activation, we report for the first time the ability of BAFF to considerably attenuate ISC differentiation of MB cells in response to CpG stimulation, a form of T cell-independent activation. Our data suggest that BAFF may be providing regulatory signals during specific T cell-independent events, which protect the balance between MB cells and ISCs outside GCs. Taken together, these data define a complex role for BAFF in humoral immune responses and show for the first time that BAFF can also play an inhibitory role in B cell differentiation.
NKT Cell Activation Mediates Neutrophil IFN-γ Production and Renal Ischemia-Reperfusion Injury
Authors: Li Li , Huang Liping , Sung Sun-sang J. , Lobo Peter I. , Brown Michael G. , Gregg Randal K. , Engelhard Victor H. , Okusa Mark D. 
Published: April 2014

Abstract
Previous work has shown that ischemia-reperfusion (IR) injury (IRI) is dependent on CD4+ T cells from naive mice acting within 24 h. We hypothesize that NKT cells are key participants in the early innate response in IRI. Kidneys from C57BL/6 mice were subjected to IRI (0.5, 1, 3, and 24 h of reperfusion). After 30 min of reperfusion, we observed a significant increase in CD4+ cells (145% of control) from single-cell kidney suspensions as measured by flow cytometry. A significant fraction of CD4+ T cells expressed the activation marker, CD69+, and adhesion molecule, LFA-1high. Three hours after reperfusion, kidney IFN-γ-producing cells were comprised largely of GR-1+CD11b+ neutrophils, but also contained CD1d-restricted NKT cells. Kidney IRI in mice administered Abs to block CD1d, or deplete NKT cells or in mice deficient of NKT cells (Jα18−/−), was markedly attenuated. These effects were associated with a significant decrease in renal infiltration and, in activation of NKT cells, and a decrease in IFN-γ-producing neutrophils. The results support the essential role of NKT cells and neutrophils in the innate immune response of renal IRI by mediating neutrophil infiltration and production of IFN-γ.