bluuebunny/crossref_metadata_2025_split huggingface dataset:
Can thiol compounds be used as biomarkers of aquatic ecosystem contamination by cadmium?
Authors: Kovářová Jana , Svobodová Zdeňka 
Published: September 2009

Can thiol compounds be used as biomarkers of aquatic ecosystem contamination by cadmium?Due to anthropogenic activities, heavy metals still represent a threat for various trophic levels. If aquatic animals are exposed to heavy metals we can obviously observe considerable toxicity. It is well known that an organism affected by cadmium (Cd) synthesize low molecular mass thiol compounds rich in cysteine (Cys), such as metallothioneins (MT) and glutathione (GSH/GSSG). The aim of this study was to summarize the effect of Cd on level of thiol compounds in aquatic organisms, and evaluate that the concentrations of thiol compounds are effective indicators of Cd water pollution and explain their potential use in biomonitoring applications.
Role of TL1A in the Pathogenesis of Rheumatoid Arthritis
Authors: Zhang Jun , Wang Xuehai , Fahmi Hassan , Wojcik Susan , Fikes James , Yu Youhua , Wu Jiangping , Luo Hongyu 
Published: September 2009

Abstract
TNF-like ligand 1A (TL1A), a member of the TNF superfamily, is the ligand of DR3 and DcR3. Several types of cells, such as endothelial cells, monocytes/macrophages, dendritic cells, and CD4 and CD8 T cells, are capable of producing this cytokine. In present study, we demonstrated that TL1A aggravated collagen-induced arthritis in mice. It increased collagen-induced arthritis penetrance and clinical scores as well as the severity of the pathological findings. TL1A administration led to the occurrence of multiple enlarged germinal centers in the spleen, and it boosted serum anti-collagen Ab titers in vivo. In vitro, TL1A augmented TNF-α production by T cells upon TCR ligation, and it greatly enhanced Th17 differentiation and IL-17 production. We further showed that human rheumatoid arthritis (RA) synovial fluids had elevated TL1A titers, and human chrondrocytes and synovial fibroblasts were capable of secreting TL1A upon TNF-α or IL-1β stimulation. Taken together, these data suggest that TL1A secretion in lymphoid organs might contribute to RA initiation by promoting autoantibody production, and TL1A secretion stimulated by inflammatory cytokines in RA joints might be a part of a vicious circle that aggravates RA pathogenesis.
The Effects of Host Age on Follicular Dendritic Cell Status Dramatically Impair Scrapie Agent Neuroinvasion in Aged Mice
Authors: Brown Karen L. , Wathne Gwennaelle J. , Sales Jill , Bruce Moira E. , Mabbott Neil A. 
Published: September 2009

Abstract
Following peripheral exposure, many transmissible spongiform encephalopathy (TSE) agents accumulate first in lymphoid tissues before spreading to the CNS (termed neuroinvasion) where they cause neurodegeneration. Early TSE agent accumulation upon follicular dendritic cells (FDCs) in lymphoid follicles appears critical for efficient neuroinvasion. Most clinical cases of variant Creutzfeldt-Jakob disease have occurred in young adults, although the reasons behind this apparent age-related susceptibility are uncertain. Host age has a significant influence on immune function. As FDC status and immune complex trapping is reduced in aged mice (600 days old), we hypothesized that this aging-related decline in FDC function might impair TSE pathogenesis. We show that coincident with the effects of host age on FDC status, the early TSE agent accumulation in the spleens of aged mice was significantly impaired. Furthermore, following peripheral exposure, none of the aged mice developed clinical TSE disease during their lifespans, although most mice displayed histopathological signs of TSE disease in their brains. Our data imply that the reduced status of FDCs in aged mice significantly impairs the early TSE agent accumulation in lymphoid tissues and subsequent neuroinvasion. Furthermore, the inefficient neuroinvasion in aged individuals may lead to significant levels of subclinical TSE disease in the population.
Long-Lived Colitogenic CD4+ Memory T Cells Residing Outside the Intestine Participate in the Perpetuation of Chronic Colitis
Authors: Nemoto Yasuhiro , Kanai Takanori , Kameyama Kaori , Shinohara Tamako , Sakamoto Naoya , Totsuka Teruji , Okamoto Ryuichi , Tsuchiya Kiichiro , Nakamura Tetsuya , Sudo Tetsuo , Matsumoto Satoshi , Watanabe Mamoru 
Published: September 2009

Abstract
To understand the perpetuation of inflammatory bowel disease (IBD), it is important to clarify whether the colitogenic CD4+ T cells are self-limited effector or long-lived memory T cells. We here investigate the latency of colitogenic CD4+ T cells in the remission stage of colitis under germfree (GF) conditions. We isolated splenic (SP) CD4+ T cells from colitic CD4+CD45RBhigh T cell-injected SCID mice maintained under specific pathogen-free (SPF) conditions and transferred them into SPF or GF SCID mice. Donor colitic SP CD4+ T cells have a characteristic CD44highCD62L−IL-7Rαhigh effector-memory T-type phenotype. Six weeks after transfer of cells to GF SCID mice, one group of mice was continued in GF conditions (GF→GF), and the other was transferred into SPF conditions (GF→SPF). GF→SPF but not GF→GF SCID mice developed colitis with elevated production of Th1 and Th17 cytokines at 4 wk after transfer. Surprisingly, a large number of CD4+ effector-memory T cells and a small but substantial number of central-memory T cells remained resident in SP and bone marrow, but not in lamina propria, of the GF→GF SCID recipients. Consistent with this, GF→SPF but not GF→GF SCID mice rapidly developed colitis. Taken together, these findings suggest that long-lived colitogenic memory CD4+ cells can be established even in the presence of commensal Ags, reside outside the intestine in the absence of commensal bacteria, and participate in the perpetuation of colitis. Thus, blocking a stimulus of colitogenic memory CD4+ cells such as IL-7 may have therapeutic benefit for treatment of inflammatory bowel disease.
Essential Impact of NF-κB Signaling on the H5N1 Influenza A Virus-Induced Transcriptome
Authors: Schmolke Mirco , Viemann Dorothee , Roth Johannes , Ludwig Stephan 
Published: September 2009

Abstract
Systemic infections of humans and birds with highly pathogenic avian influenza A viruses of the H5N1 subtype are characterized by inner bleedings and a massive overproduction of cytokines known as cytokine storm. Growing evidence supports the role of endothelial cells in these processes. The aim of this study was to elucidate determinants of this strong response in endothelial cells with a focus on the transcription factor NF-κB. This factor is known as a major regulator of inflammatory response; however, its role in influenza virus replication and virus-induced immune responses is controversially discussed. By global mRNA profiling of infected cells in the presence or absence of a dominant negative mutant of IκB kinase 2 that specifically blocks the pathway, we could show that almost all H5N1 virus-induced genes depend on functional NF-κB signaling. In particular, activation of NF-κB is a bottleneck for the expression of IFN-β and thus influences the expression of IFN-dependent genes indirectly in the primary innate immune response against H5N1 influenza virus. Control experiments with a low pathogenic influenza strain revealed a much weaker and less NF-κB-dependent host cell response.
Mitochondrial Dysfunction Increases Allergic Airway Inflammation
Authors: Aguilera-Aguirre Leopoldo , Bacsi Attila , Saavedra-Molina Alfredo , Kurosky Alexander , Sur Sanjiv , Boldogh Istvan 
Published: September 2009

Abstract
The prevalence of allergies and asthma among the world’s population has been steadily increasing due to environmental factors. It has been described that exposure to ozone, diesel exhaust particles, or tobacco smoke exacerbates allergic inflammation in the lungs. These environmental oxidants increase the levels of cellular reactive oxygen species (ROS) and induce mitochondrial dysfunction in the airway epithelium. In this study, we investigated the involvement of preexisting mitochondrial dysfunction in the exacerbation of allergic airway inflammation. After cellular oxidative insult induced by ragweed pollen extract (RWE) exposure, we have identified nine oxidatively damaged mitochondrial respiratory chain-complex and associated proteins. Out of these, the ubiquinol-cytochrome c reductase core II protein (UQCRC2) was found to be implicated in mitochondrial ROS generation from respiratory complex III. Mitochondrial dysfunction induced by deficiency of UQCRC2 in airway epithelium of sensitized BALB/c mice prior the RWE challenge increased the Ag-induced accumulation of eosinophils, mucin levels in the airways, and bronchial hyperresponsiveness. Deficiency of UQCRC1, another oxidative damage-sensitive complex III protein, did not significantly alter cellular ROS levels or the intensity of RWE-induced airway inflammation. These observations suggest that preexisting mitochondrial dysfunction induced by oxidant environmental pollutants is responsible for the severe symptoms in allergic airway inflammation. These data also imply that mitochondrial defects could be risk factors and may be responsible for severe allergic disorders in atopic individuals.
Dendritic Cells Support the In Vivo Development and Maintenance of NK Cells via IL-15 Trans-Presentation
Authors: Castillo Eliseo F. , Stonier Spencer W. , Frasca Loredana , Schluns Kimberly S. 
Published: September 2009

Abstract
IL-15 is a key component that regulates the development and homeostasis of NK cells and is delivered through a mechanism termed trans-presentation. During development, multiple events must proceed to generate a functional mature population of NK cells that are vital for tumor and viral immunity. Nevertheless, how IL-15 regulates these various events and more importantly what cells provide IL-15 to NK cells to drive these events is unclear. It is known dendritic cells (DC) can activate NK cells via IL-15 trans-presentation; however, the ability of DC to use IL-15 trans-presentation to promote the development and homeostatic maintenance of NK cell has not been established. In this current study, we show that IL-15 trans-presentation solely by CD11c+ cells assists the in vivo development and maintenance of NK cells. More specifically, DC-mediated IL-15 trans-presentation drove the differentiation of NK cells, which included the up-regulation of the activating and inhibitory Ly49 receptors. Although these cells did not harbor a mature CD11bhigh phenotype, they were capable of degranulating and producing IFN-γ upon stimulation similar to wild-type NK cells. In addition, DC facilitated the survival of mature NK cells via IL-15 trans-presentation in the periphery. Thus, an additional role for NK-DC interactions has been identified whereby DC support the developmental and homeostatic niche of NK cells.
Differential Effect of IL-27 on Developing versus Committed Th17 Cells
Authors: El-behi Mohamed , Ciric Bogoljub , Yu Shuo , Zhang Guang-Xian , Fitzgerald Denise C. , Rostami Abdolmohamad 
Published: September 2009

Abstract
IL-27 counters the effect of TGF-β+IL-6 on naive CD4+ T cells, resulting in near complete inhibition of de novo Th17 development. In contrast, little is known about the effect of IL-27 on already differentiated Th17 cells. A better understanding of how IL-27 regulates these cells is needed to evaluate the therapeutic potential of IL-27 in Th17 cells-associated diseases. In this study, we show that IL-27 had surprisingly little effect on committed Th17 cells, despite its expression of a functional IL-27R. Contrary to de novo differentiation of Th17 cells, IL-27 did not suppress expression of retinoid-related orphan receptor (ROR)γt or RORα in committed Th17 cells. Consistent with this finding, the frequency of committed Th17 cells and their cytokine secretion remained unaffected by IL-27. Both memory Th17 cells (CD4+CD25−CD62Llow) that developed in vivo and encephalitogenic Th17 cells infiltrating the CNS of mice developing experimental autoimmune encephalomyelitis produced similar amounts of IL-17A when reactivated with IL-23 in the absence and presence of exogenous IL-27. Finally, IL-27 failed to suppress encephalitogenicity of Th17 cells in an adoptive transfer of experimental autoimmune encephalomyelitis. Analysis ex vivo of transferred Th17 cells in the spleen and CNS of recipient mice showed that cells retained similar phenotype irrespective of whether cells were treated or not with IL-27. Our data demonstrate that in contrast to inhibition of de novo differentiation of Th17 cells, IL-27 has little or no effect on committed Th17 cells. These findings indicate that therapeutic applications of IL-27 might have a limited efficacy in inflammatory conditions where aggressive Th17 responses have already developed.
DrosophilaGlycoprotein 93 Is an Ortholog of Mammalian Heat Shock Protein gp96 (grp94, HSP90b1, HSPC4) and Retains Disulfide Bond-Independent Chaperone Function for TLRs and Integrins
Authors: Morales Crystal , Wu Shuang , Yang Yi , Hao Bing , Li Zihai 
Published: September 2009

AbstractMammalian heat shock protein gp96 is an obligate chaperone for multiple integrins and TLRs, the mechanism of which is largely unknown. We have identified gp93 in Drosophila having high sequence homology to gp96. However, no functions were previously attributed to gp93. To determine whether gp93 and gp96 are functionally conserved, we have expressed gp93 in gp96-deficient mouse cells. Remarkably, the Drosophila gp93 is able to chaperone multiple murine gp96 clients including integrins α4, αL, and β2 and TLR2 and TLR9. This observation has led us to examine the structural basis of the chaperone function of gp96 by a close comparison between gp96 and gp93. We report that whereas gp96 undergoes intermolecular disulfide bond formation via Cys138, gp93 is unable to do so due to the absence of a cysteine near the same region. However, abrogation of disulfide bond formation by substituting C with A (C138A) in gp96 via site-directed mutagenesis did not compromise its chaperone function. Likewise, gp93 chaperone ability could not be improved by forcing intermolecular bond formation between gp93 N termini. We conclude that gp93 is the Drosophila ortholog of gp96 and that the chaperone function of the two molecules is conserved. Moreover, gp96 N-terminal disulfide bond formation is not critical for its function, underscoring the importance of N-terminal dimerization via non-disulfide bond-mediated interactions in client protein folding by gp96. Further study of gp96 from an evolutionary angle shall be informative to uncover the detailed mechanism of its chaperone function of client proteins in the secretory pathway.
Enhanced Dendritic Cell-Induced Immune Responses Mediated by the Novel C-Type Lectin Receptor mDCAR1
Authors: Kaden Stefan A. , Kurig Stefanie , Vasters Katrin , Hofmann Kay , Zaenker Kurt S. , Schmitz Juergen , Winkels Gregor 
Published: September 2009

AbstractThe dendritic cell (DC) immunoreceptors (DCIR) and DC-immunoactivating receptors (DCAR) represent a subfamily of cell surface C-type lectin receptors (CLR), whose multifunctional capacities range from classical Ag uptake and immunoregulatory mechanisms to the involvement in DC ontogeny. On the basis of the generation of specific mAbs, we functionally characterized mouse DCAR1 (mDCAR1) as a member of the DCIR/DCAR family. Expression of mDCAR1 was strongly tissue dependent. mDCAR1 expression on DCs was restricted to the CD8+ DC subset in spleen and thymus and on subpopulations of CD11b+ myeloid cells in bone marrow and spleen, whereas the molecule was not detectable on both cell types in lymph nodes and peripheral blood. With respect to the function of CLRs as pattern recognition receptors, Ag delivered via mDCAR1 was internalized, was trafficked to early and late endosomes/lysosomes and, as a consequence, induced cellular and humoral responses in vivo even in the absence of CD40 stimulation. Intriguingly, upon triggering mDCAR1, CD8+ DCs increased the secretion of bioactive IL-12, whereas IL-10 release is markedly reduced, thereby indicating that Ag recognized by mDCAR1 induces enhanced proinflammatory responses. These data indicate that mDCAR1 is a functional receptor on cells of the immune system and provides further insights into the regulation of immune responses by CLRs.
Cutting Edge: OX40 Agonists Can Drive Regulatory T Cell Expansion if the Cytokine Milieu Is Right
Authors: Ruby Carl E. , Yates Melissa A. , Hirschhorn-Cymerman Daniel , Chlebeck Peter , Wolchok Jedd D. , Houghton Alan N. , Offner Halina , Weinberg Andrew D. 
Published: September 2009

Abstract
We report that OX40 stimulation drives all lineages of CD4 T cell development, including regulatory T cells (Tregs), and the plasticity of the response is dependant on local cytokines. In TGF-β1-treated cultures, an OX40 agonist increased IFN-γ and IL-4 production and diverted T cells from the Treg lineage. However, cytokine blockade in the context of OX40 stimulation promoted enhanced Treg accumulation. This observation was evident in naive mice, as OX40 engagement enhanced Treg proliferation and accumulation in vivo. Lastly, OX40 agonist administration influenced experimental autoimmune encephalomyelitis disease severity in opposing directions, depending on the timing of administration. Given during Ag priming, the OX40 agonist drove Treg expansion and inhibited disease, whereas given later it enhanced T cell effector cytokine production in the CNS and exacerbated disease. Hence, OX40 signaling can augment the accumulation of all CD4 T cell lineages; however, its accentuation of immune responses may have vastly different biologic outcomes depending upon the local cytokine milieu.
Role of Endothelial TLR4 for Neutrophil Recruitment into Central Nervous System Microvessels in Systemic Inflammation
Authors: Zhou Hong , Andonegui Graciela , Wong Connie H. Y. , Kubes Paul 
Published: September 2009

AbstractBrain inflammation is a frequent consequence of sepsis and septic shock. We imaged leukocyte recruitment in brain postcapillary venules induced by i.p. administration of LPS as a simple model of systemic inflammation. The i.p. injection of LPS (0.5 mg/kg) induced significant leukocyte rolling and adhesion in brain postcapillary venules of wild-type (WT) mice and more than 90% were neutrophils. However, no emigrated neutrophils were detected in brain parenchyma. High levels of TNF-α and IL-1β were detected in the plasma after LPS injection but a different profile (IL-1β but not TNF-α) was detected in the brain. LPS caused no recruitment in TLR4 knockout mice. In chimeric mice with TLR4-expressing resident cells but TLR4-deficient bone marrow-derived circulating cells, neutrophil rolling and adhesion was similar to WT mice. This observation is consistent with a requirement for resident cells in the LPS-induced neutrophil recruitment into brain microvessels. Transgenic mice engineered to express TLR4 exclusively on endothelial cells had a similar level of leukocyte recruitment in brain as WT mice in response to LPS. High dose LPS (10 mg/kg) led to neutrophil infiltration in the brain parenchyma in WT mice. High KC and MIP-2 production was observed from brain parenchyma microglial cells, and CXCR2 knockout mice failed to recruit neutrophils. However, neither neutrophil infiltration nor KC or MIP-2 was observed in endothelial TLR4 transgenic mice in response to this LPS dose. Our results demonstrate that direct endothelial activation is sufficient to mediate leukocyte rolling and adhesion in cerebral microvessels but not sufficient for emigration to brain parenchyma.
Evidence for Local Expansion of IgA Plasma Cell Precursors in Human Ileum
Authors: Yuvaraj Saravanan , Dijkstra Gerard , Burgerhof Johannes G. M. , Dammers Peter M. , Stoel Maaike , Visser Annie , Kroese Frans G. M. , Bos Nicolaas A. 
Published: September 2009

Abstract
IgA plays a crucial role in establishment and maintenance of mucosal homeostasis between host cells and commensal bacteria. To this end, numerous IgA plasma cells are located in the intestinal lamina propria. Whether the (immediate) precursor cells for these plasma cells can expand locally is not completely known and was studied here. The total number of IgA plasma cells in human ileal biopsies was counted. Sequence analysis of IgA VH genes from human ileal biopsies revealed the occurrence of many clonally related sequences within a biopsy, but not between different biopsies. This observation strongly argues for local expansion of IgA precursor cells. By comparing the number of unique sequences with the number of clonally related sequences within a biopsy, we estimated that ∼100–300 precursors were responsible for the 75,000 IgA-producing cells that were present per biopsy. These precursor cells must therefore have divided locally 9–10 times. Since all sequences contained mutations and most of the mutations present in clonally related sequences were shared, the IgA precursor cells must have arrived initially as mutated cells in the lamina propria. Our data show evidence for the existence of two waves of expansion for IgA-producing cells in human ileum. The first wave occurs during initial stimulation in germinal centers as evidenced by somatic hypermutations. A second wave of expansion of IgA-committed cells occurs locally within the lamina propria as evidenced by the high frequency of clonally related cells.
Lessons from Thymic Epithelial Heterogeneity: FoxN1 and Tissue-Restricted Gene Expression by Extrathymic, Endodermally Derived Epithelium
Authors: Dooley James , Erickson Matthew , Farr Andrew G. 
Published: September 2009

Abstract
Modeling of thymic epithelial differentiation has been guided by several important underlying assumptions. One is that within epithelial tissues derived from pharyngeal endoderm, FoxN1 expression is signature for the thymic epithelial lineage. Another is that expression of tissue-restricted Ag (TRA) is a unique feature of thymic epithelium. In this murine study, we evaluate the thymic expression of a subset of TRA, parathyroid hormone, calcitonin, and thyroglobulin, as part of an effort to better define the heterogeneity of medullary thymic epithelial cells. In this study, we demonstrate that both conventional and cystic epithelial cells display a history of FoxN1 expression using a cre-lox approach. We also document that extrathymic epithelial tissues that originate from pharyngeal endoderm also have a history of FoxN1 expression, indicating that FoxN1 expression per se is not a signature for the thymic lineage and suggesting that FoxN1 expression, whereas necessary for thymic epithelium, development, is not sufficient for this process to occur. Both cystic and conventional medullary thymic epithelial cells express these TRAs, as do extrathymic epithelial tissues that are not usually considered to be sources of these molecules. This finding supports the proposition that promiscuous gene expression is not unique to the thymus. Furthermore, the pattern of promiscuous gene expression in these extrathymic epithelia is consistent with developmental regulation processes and suggests that it is premature to discard the possibility that some promiscuous gene expression in the thymus reflects normal differentiation programs of epithelia.