bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antagonistic Effects of TNF-α on TGF-β Signaling Through Down-Regulation of TGF-β Receptor Type II in Human Dermal Fibroblasts
Authors: Yamane Kenichi , Ihn Hironobu , Asano Yoshihide , Jinnin Masatoshi , Tamaki Kunihiko 
Published: April 2014

Abstract
Transforming growth factor-β stimulates the production of the extracellular matrix, whereas TNF-α has antifibrotic activity. Understanding the molecular mechanism underlying the antagonistic activities of TNF-α against TGF-β is critical in the context of tissue repair and maintenance of tissue homeostasis. In the present study, we demonstrated a novel mechanism by which TNF-α blocks TGF-β-induced gene and signaling pathways in human dermal fibroblasts. We showed that TNF-α prevents TGF-β-induced gene trans activation, such as α2(I) collagen or tissue inhibitor of metalloproteinases 1, and TGF-β signaling pathways, such as Smad3, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinases, without inducing levels of inhibitory Smad7 in human dermal fibroblasts. TNF-α down-regulates the expression of type II TGF-β receptor (TβRII) proteins, but not type I TGF-β receptor (TβRI), in human dermal fibroblasts. However, neither TβRII mRNA nor TβRII promoter activity was decreased by TNF-α. TNF-α-mediated decrease of TβRII protein expression was not inhibited by the treatment of fibroblasts with either a selective inhibitor of I-κB-α phosphorylation, BAY 11-7082, or a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, PD98059. Calpain inhibitor I (ALLN), a protease inhibitor, inhibits TNF-α-mediated down-regulation of TβRII. We found that TNF-α triggered down-regulation of TβRII, leading to desensitization of human dermal fibroblasts toward TGF-β. Furthermore, these events seemed to cause a dramatic down-regulation of α2(I) collagen and tissue inhibitor of metalloproteinases 1 in systemic sclerosis fibroblasts. These results indicated that TNF-α impaired the response of the cells to TGF-β by regulating the turnover of TβRII.
The Sgp3 Locus on Mouse Chromosome 13 Regulates Nephritogenic gp70 Autoantigen Expression and Predisposes to Autoimmunity
Authors: Laporte Catherine , Ballester Benoît , Mary Charles , Izui Shozo , Reininger Luc 
Published: April 2014

Abstract
By interval mapping of a backcross progeny between New Zealand White (NZW) and C57BL/6 (B6) mice bearing the Y chromosome-linked autoimmune acceleration gene Yaa, we previously identified a genetic locus on mid-chromosome 13, here designated as Sgp3, showing a major effect on the expression of a nephritogenic autoantigen, gp70. In this study, the NZW-derived Sgp3 region was transferred by backcross procedure and marker-assisted selection on the B6 background to produce three independent congenic strains B6.NZW-Sgp3/1, -Sgp3/2, and -Sgp3/3. We show that NZW homozygosity at a single 3 centiMorgans (∼12 megabases (Mb)) interval between markers D13Mit142 and D13Mit254 mediates increased basal serum levels of gp70 in B6.NZW-Sgp3/1 and B6.NZW-Sgp3/2 mice and with a higher degree in males (∼15 μg/ml) than in females (∼9 μg/ml) as compared with B6 (∼2 μg/ml), revealing a gender effect. However, their gp70 levels are still lower than that of NZW mice (∼60 μg/ml). In addition, B6.NZW-Sgp3/1 and B6.NZW-Sgp3/2 mice showed a moderate 2- to 3-fold increase in serum gp70 in response to LPS, which contrasted with over a 10-fold increase in NZW mice. Although both B6.NZW-Sgp3/1 and B6.NZW-Sgp3/2 mice failed to produce significant amounts of gp70 anti-gp70 immune complexes, unexpectedly, aged B6.NZW-Sgp3/2 congenic males bearing the Yaa gene developed increased titers of IgG autoantibodies to DNA and chromatin. Our data indicate that Sgp3 is involved in a complex process of gp70 production under polygenic control and may provide a significant contribution to lupus susceptibility not only through up-regulation of gp70 autoantigen production but also predisposition to autoimmunity.
Molecular Signatures of Anti-nuclear Antibodies: Contributions of Specific Light Chain Residues and a Novel New Zealand BlackVκ1Germline Gene
Authors: Liang Zhiyan , Chen Cui , Mohan Chandra 
Published: April 2014

AbstractAlthough the Ig H chains of anti-nuclear Abs (ANA) have been described to possess certain shared molecular signatures, it remains unclear whether the L chains of these Abs also possess distinctive molecular features. The present study examines this by generating and analyzing two comprehensive murine Ig L chain databases, one consisting of 264 monoclonal ANAs and the other consisting of 145 non-ANAs, drawn from previously published work. Importantly, clonal replicates were represented only once each, so as to minimize bias. ANAs and non-ANAs did not differ in Vκ family or Jκ gene usage, nor in their mutation frequencies. Interestingly, the L chains of ANAs exhibited differential usage of certain complementarity-determining region residues, arising almost entirely from the increased usage of certain Vκ germline genes, notably, Vκ ai4 among anti-dsDNA ANAs, Vκ23–45 among anti-ssDNA ANAs, and Vκ21–12 among non-ANAs. Finally, prompted by the increased prevalence of a particular Vκ1 family sequence among ANAs, we proceeded to clone a novel New Zealand Black Vκ1 germline gene, named bb1.1, which appears to be frequently used to encoded anti-ssDNA Abs. Collectively, these studies underline the potential contribution of particular Vκ germline genes in promoting or thwarting DNA binding.
Specific Inhibition of Stat5a/b Promotes Apoptosis of IL-2-Responsive Primary and Tumor-Derived Lymphoid Cells
Authors: Behbod Fariba , Nagy Zsuzsanna S. , Stepkowski Stanislaw M. , Karras James , Johnson Charlene R. , Jarvis W. David , Kirken Robert A. 
Published: April 2014

AbstractStat5a/b exhibits 96% homology and are required for normal immune function. The present studies examined Stat5a/b function in lymphoid cells by specific and simultaneous disruption of both proteins using novel phosphorothioate-2′-O-methoxyethyl antisense oligodeoxynucleotides (asODN). Efficient delivery was confirmed by the presence of fluorescent TAMRA-labeled ODN in ≥55 and 95% in human primary and tumor cell lines, respectively. Acute asODN administration reduced levels of Stat5a (90%) in 6 h, whereas Stat5b required nearly 48 h to attain the same inhibition, suggesting that the apparent turnover rate for Stat5a was 8-fold higher than that for Stat5b. Expression of the closely related Stat3 protein was unchanged after asODN treatment, however. Molecular ablation of Stat5a/b promoted apoptotic cell death in a significant population of primary PHA-activated T cells (72%) and lymphoid tumor cell line (e.g., YT; 74%) within 24 h, as assessed by 1) visualization of karyolytic nuclear degeneration and other generalized cytoarchitectural alterations, 2) enzymatic detection of TdT-positive DNA degradation, and 3) automated cytometric detection of annexin V translocation. Contrary to findings from Stat5a/b-null mice, cell cycle progression did not appear to be significantly affected. Interestingly, IL-2-insensitive and unprimed T cells and Jurkat cells remained mostly unaffected. Finally, evidence is provided that the cytotoxicity associated with Stat5a/b ablation may derive from activation of caspase-8, an initiator protease that contributes to apoptotic cell commitment. We propose that in lymphoid cells competent to activate Stat5a and Stat5b, both proteins preferentially mediate an antiapoptotic survival influence.
Different Dynamics of CD4+ and CD8+ T Cell Responses During and After Acute Lymphocytic Choriomeningitis Virus Infection
Authors: De Boer Rob J. , Homann Dirk , Perelson Alan S. 
Published: April 2014

Abstract
We fit a mathematical model to data characterizing the primary cellular immune response to lymphocytic choriomeningitis virus. The data enumerate the specific CD8+ T cell response to six MHC class I-restricted epitopes and the specific CD4+ T cell responses to two MHC class II-restricted epitopes. The peak of the response occurs around day 8 for CD8+ T cells and around day 9 for CD4+ T cells. By fitting a model to the data, we characterize the kinetic differences between CD4+ and CD8+ T cell responses and among the immunodominant and subdominant responses to the various epitopes. CD8+ T cell responses have faster kinetics in almost every aspect of the response. For CD8+ and CD4+ T cells, the doubling time during the initial expansion phase is 8 and 11 h, respectively. The half-life during the contraction phase following the peak of the response is 41 h and 3 days, respectively. CD4+ responses are even slower because their contraction phase appears to be biphasic, approaching a 35-day half-life 8 days after the peak of the response. The half-life during the memory phase is 500 days for the CD4+ T cell responses and appears to be lifelong for the six CD8+ T cell responses. Comparing the responses between the various epitopes, we find that immunodominant responses have an earlier and/or larger recruitment of precursors cells before the expansion phase and/or have a faster proliferation rate during the expansion phase.
Prostaglandin D2 Inhibits Airway Dendritic Cell Migration and Function in Steady State Conditions by Selective Activation of the D Prostanoid Receptor 1
Authors: Hammad Hamida , Jan de Heer Hendrik , Soullie Thomas , Hoogsteden Henk C. , Trottein Francois , Lambrecht Bart N. 
Published: April 2014

AbstractPGD2 is the major mediator released by mast cells during allergic responses, and it acts through two different receptors, the D prostanoid receptor 1 (DP1) and DP2, also known as CRTH2. Recently, it has been shown that PGD2 inhibits the migration of epidermal Langerhans cells to the skin draining lymph nodes (LNs) and affects the subsequent cutaneous inflammatory reaction. However, the role of PGD2 in the pulmonary immune response remains unclear. Here, we show that the intratracheal instillation of FITC-OVA together with PGD2 inhibits the migration of FITC+ lung DC to draining LNs. This process is mimicked by the DP1 agonist BW245C, but not by the DP2 agonist DK-PGD2. The ligation of DP1 inhibits the migration of FITC-OVA+ DCs only temporarily, but still inhibits the proliferation of adoptively transferred, OVA-specific, CFSE-labeled, naive T cells in draining LNs. These T cells produced lower amounts of the T cell cytokines IL-4, IL-10, and IFN-γ compared with T cells from mice that received FITC-OVA alone. Taken together, our data suggest that the activation of DP receptor by PGD2 may represent a pathway to control airway DC migration and to limit the activation of T cells in the LNs under steady state conditions, possibly contributing to homeostasis in the lung.
Mediation of Enhanced Transcription of the IL-10 Gene in T Cells, Upon Contact with Human Glioma Cells, by Fas Signaling Through a Protein Kinase A-Independent Pathway
Authors: Yang Bei-Chang , Lin Heng-Kai , Hor Wei-Shio , Hwang Jun-Yen , Lin Yu-Ping , Liu Ming-Yie , Wang Ying-Jan 
Published: April 2014

AbstractElevated expression of IL-10 has been frequently observed in tumor tissues and tumor-infiltrating cells. We show herein that transcription of the IL-10 gene in primary peripheral T cells and T cell lines is up-regulated upon contact with glioma cells without an induction of apoptosis in those T cells. Glioma-associated IL-10 induction was suppressed by interrupting the engagement of Fas and its ligand (Fas-L) with the antagonistic Ab, ZB4, by reducing Fas-L expression of glioma cells using the Fas-L-specific ribozyme, or by preventing cell-to-cell contact in a Transwell culture setting. Cross-linking of Fas with the agonistic Ab, CH-11, triggered apoptosis and enhanced the expression of IL-10 in Jurkat cells at the transcriptional and translational levels. Inhibiting caspase activities by caspase inhibitors, Z-VAD (Z-Val-Ala-Asp(Ome)-fluoromethylketone) and Z-IETD (Z-Ile-Glu(Ome)-Thr(Ome)-Asp(Ome)-fluoromethylketone), abolished this IL-10 induction in Jurkat cells. Intracellular staining detected IL-10 proteins in Fas-cross-linked Jurkat cells and in PHA-activated T cells. However, few IL-10 proteins were detectable in Jurkat cells cocultured with glioma cells, indicating a requirement of other factors for IL-10 production. Direct activation of protein kinase A (PKA) by forskolin elevated the transcription of IL-10 in Jurkat cells. However, KT5720, a selective PKA inhibitor, reduced neither anti-Fas-triggered nor glioma-associated IL-10 expression. Phosphorylation of cAMP response element binding protein and activating transcription factor-1 in Jurkat cells was not affected by coculturing with glioma cells or by anti-Fas treatment, further suggesting a PKA-independent pathway. In summary, our results demonstrate nonlethal cross-talk between tumor and immune cells leading to IL-10 dysregulation in T cells, which might contribute to Fas-L+ tumor-associated immunosuppression.
Functional Effects of TNF-α on a Human Follicular Dendritic Cell Line: Persistent NF-κB Activation and Sensitization for Fas-Mediated Apoptosis
Authors: Park Sun-Mi , Park Hae-Young , Lee Tae H. 
Published: April 2014

AbstractFollicular dendritic cells (FDC) play crucial roles in germinal center (GC) formation and differentiation of GC B cells. FDC functions are influenced by cytokines produced in the GC. Among the GC cytokines, TNF is known to be essential for the formation and maintenance of the FDC network in the GC. We found that TNF is a mitogenic growth factor to an established FDC-like cell line, HK cells. Differing from most cell types which become desensitized to TNF action, HK cells exhibited persistent TNF signaling, as demonstrated by prolonged and biphasic NF-κB activation even after 3 days of TNF treatment. As a result, antiapoptotic genes including TNFR-associated factors 1 and 2, and cellular inhibitor of apoptosis proteins 1 and 2 were persistently induced by TNF, leading to the protection against TNF-mediated cell death. However, TNF pretreatment enhanced Fas-mediated apoptosis by up-regulating surface Fas expression in an NF-κB-dependent pathway. During the GC responses, proliferation followed by FDC death has not been documented. However, our in vitro results suggest that FDCs proliferate in response to TNF, and die by Fas-mediated apoptosis whose susceptibility is enhanced by TNF, representing a mode of action for TNF in the maintenance of FDC networks by regulating the survival or death of FDC.
Regulation of Developing B Cell Survival by RelA-Containing NF-κB Complexes
Authors: Prendes Maria , Zheng Ye , Beg Amer A. 
Published: April 2014

Abstract
Mice deficient in the RelA (p65) subunit of NF-κB die during embryonic development. Fetal liver (FL) hemopoietic precursors from these mice were used to generate RelA-deficient lymphocytes by adoptive transfer into lethally irradiated mature lymphocyte-deficient recombination-activating gene-1−/− mice. Strikingly, RelA−/− lymphocyte generation was greatly diminished compared with that of RelA+/+ lymphocytes. The most dramatic reduction was noticed in the numbers of developing B cells, which were considerably increased when RelA−/− FL cells that were also TNFR1 deficient were used. The role of RelA was further investigated in FL-derived developing B cells in vitro. Our results show that RelA is a major component of constitutive and TNF-α-induced κB site-binding activity in developing B cells, and provide evidence for a direct role of TNF-α in killing RelA−/− B cells. The absence of RelA significantly reduced mRNA expression of the antiapoptotic genes cellular FLICE-inhibitory protein and Bcl-2. Retroviral transduction of RelA−/− B cells with either cFLIP or Bcl-2 significantly reduced TNF-α killing. Together, these results indicate that RelA plays a crucial role in regulating developing B cell survival by inhibiting TNF-α cytotoxicity.
Expression and Function of Toll-Like Receptors in Eosinophils: Activation by Toll-Like Receptor 7 Ligand
Authors: Nagase Hiroyuki , Okugawa Shu , Ota Yasuo , Yamaguchi Masao , Tomizawa Hideyuki , Matsushima Kouji , Ohta Ken , Yamamoto Kazuhiko , Hirai Koichi 
Published: April 2014

Abstract
We investigated the expression of a panel of Toll-like receptors (TLRs) and their functions in human eosinophils. Eosinophils constitutively expressed TLR1, TLR4, TLR7, TLR9, and TLR10 mRNAs (TLR4 greater than TLR1, TLR7, TLR9, and TLR10 greater than TLR6). In contrast, neutrophils expressed a larger variety of TLR mRNAs (TLR1, TLR2, TLR4, TLR6, TLR8 greater than TLR5, TLR9, and TLR10 greater than TLR7). Although the expression levels in eosinophils were generally less prominent compared with those in neutrophils, eosinophils expressed a higher level of TLR7. Furthermore, among various TLR ligands (S-(2,3-bis(palmitoyloxy)-(2-RS)-propyl)-N-palmitoyl-Cys-Ser-(Lys)4, poly(I:C), LPS, R-848, and CpG DNA), only R-848, a ligand of TLR7 and TLR8, regulated adhesion molecule (CD11b and L-selectin) expression, prolonged survival, and induced superoxide generation in eosinophils. Stimulation of eosinophils by R-848 led to p38 mitogen-activated protein kinase activation, and SB203580, a p38 mitogen-activated protein kinase inhibitor, almost completely attenuated R-848-induced superoxide generation. Although TLR8 mRNA expression was hardly detectable in freshly isolated eosinophils, mRNA expression of TLR8 as well as TLR7 was exclusively up-regulated by IFN-γ but not by either IL-4 or IL-5. The up-regulation of the TLRs by IFN-γ had potentially functional significance: the extent of R-848-induced modulation of adhesion molecule expression was significantly greater in cells treated with IFN-γ compared with untreated cells. Although the natural ligands for TLR7 and TLR8 have not yet been identified, our results suggest that eosinophil TLR7/8 systems represent a potentially important mechanism of a host-defensive role against viral infection and mechanism linking exacerbation of allergic inflammation and viral infection.
Broadly Increased Sensitivity to Cytotoxic T Lymphocytes Resulting from Nef Epitope Escape Mutations
Authors: Ali Ayub , Pillai Satish , Ng Hwee , Lubong Rachel , Richman Douglas D. , Jamieson Beth D. , Ding Yan , McElrath M. Juliana , Guatelli John C. , Yang Otto O. 
Published: April 2014

Abstract
Nef is an HIV-1 protein that is absent in most retroviruses, yet its reading frame is highly maintained despite frequent targeting by CD8+ CTL in vivo. Because Nef is not necessarily required for viral replication, this consistent maintenance suggests that Nef plays an important role(s) and substantial fitness constraints prevent its loss in vivo. The ability of Nef to down-regulate cell surface MHC class I (MHC-I) molecules and render infected cells resistant to CTL in general is likely to be an important contributing function. We demonstrate that mutational escape of HIV-1 from Nef-specific CTL in vitro leads to progeny virions that are increased in their susceptibility to CTL of specificities for proteins other than Nef. The escape mutants contain multiple nef mutations that impair the ability of the virus to down-regulate MHC-I through disruption of its reading frame as well as epitope point mutations. Given the rarity of nef frameshifts in vivo, these data support the concept that the ability to down-regulate MHC-I could be a key constraint for preservation of Nef in vivo.
Glycolipid Antigen Drives Rapid Expansion and Sustained Cytokine Production by NK T Cells
Authors: Crowe Nadine Y. , Uldrich Adam P. , Kyparissoudis Konstantinos , Hammond Kirsten J. L. , Hayakawa Yoshihiro , Sidobre Stephané , Keating Rachael , Kronenberg Mitchell , Smyth Mark J. , Godfrey Dale I. 
Published: April 2014

Abstract
NKT cells are enigmatic lymphocytes that respond to glycolipid Ags presented by CD1d. Although they are key immunoregulatory cells, with a critical role in immunity to cancer, infection, and autoimmune diseases, little is known about how they respond to antigenic challenge. Current theories suggest that NKT cells die within hours of stimulation, implying that their direct impact on the immune system derives from the initial cytokine burst released before their death. Here we show that NKT cell disappearance results from TCR down-regulation rather than apoptosis, and that they expand to many times their normal number in peripheral tissues within 2–3 days of stimulation, before contracting to normal numbers over subsequent days. This expansion is associated with ongoing cytokine production, biased toward a Th1 (IFN-γ+ IL-4−) phenotype, in contrast to their initial Th0 (IFN-γ+IL-4+) phenotype. This study provides critical new insight into how NKT cells can have such a major impact on immune responses, lasting many days beyond the initial stimulation of these cells.
Dynamics of Pathogenic and Suppressor T Cells in Autoimmune Diabetes Development
Authors: Gregori Silvia , Giarratana Nadia , Smiroldo Simona , Adorini Luciano 
Published: April 2014

Abstract
In the nonobese diabetic (NOD) mouse, pathogenic and suppressor CD4+ T cells can be distinguished by the constitutive expression of CD25. In this study, we demonstrate that the progression of autoimmune diabetes in NOD mice reflects modifications in both T cell subsets. CD4+CD25+ suppressor T cells from 8-, but not 16-wk-old NOD mice delayed the onset of diabetes transferred by 16-wk-old CD25-depleted spleen cells. These results were paralleled by the inhibition of alloantigen-induced proliferation of CD4+CD25− cells, indicating an age-dependent decrease in suppressive activity. In addition, CD4+CD25− pathogenic T cells became progressively less sensitive to immunoregulation by CD4+CD25+ T cells during diabetes development. CD4+CD25− T cells showed a higher proliferation and produced more IFN-γ, but less IL-4 and IL-10, whereas CD4+CD25+ T suppressor cells produced significantly lower levels of IL-10 in 16- compared with 8-wk-old NOD mice. Consistent with these findings, a higher frequency of Th1 cells was observed in the pancreas of 16-wk-old compared with 8-wk-old NOD mice. An increased percentage of CD4+CD25− T cells expressing CD54 was present in 16-wk-old and in diabetic NOD, but not in BALB/c mice. Costimulation via CD54 increased the proliferation of CD4+CD25− T cells from 16-, but not 8-wk-old NOD mice, and blocking CD54 prevented their proliferation, consistent with the role of CD54 in diabetes development. Thus, the pathogenesis of autoimmune diabetes in NOD mice is correlated with both an enhanced pathogenicity of CD4+CD25− T cells and a decreased suppressive activity of CD4+CD25+ T cells.
The Central Tolerance Response to Male Antigen in Normal Mice Is Deletion and Not Receptor Editing
Authors: Holman Philmore O. , Walsh Elizabeth R. , Hogquist Kristin A. 
Published: April 2014

Abstract
It is widely accepted that developing T cells can undergo clonal deletion in the thymus in response to a high affinity self-Ag. This is largely based on studies of TCR transgenics. However, encounter with high affinity self-Ag can also result in receptor editing in TCR transgenic models. Because all TCR transgenics display ectopic receptor expression, the tolerance mechanism that predominates in normal mice remains an open question. When self-Ag drives receptor editing during T cell development, one expects to find in-frame, self-reactive TCRα joins on TCR excision circles (TRECs), which are the products of secondary V/J recombination in the TCRα locus. Such joins are not expected if clonal deletion occurs, because the progenitor cell would be eliminated by apoptosis. To test the relative utilization of receptor editing vs clonal deletion, we determined the frequency of in-frame, male-specific joins on TRECs in male and female HYβ transgenic mice. In comparison with female HYβ transgenic mice, our analysis showed a lower frequency of TRECs with male-reactive V17J57 joins in male mice. Thus, it would appear that receptor editing is not a predominant tolerance mechanism for this self-Ag.