bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced Th2 Cell-Mediated Allergic Inflammation in Tyk2-Deficient Mice
Authors: Seto Yohei , Nakajima Hiroshi , Suto Akira , Shimoda Kazuya , Saito Yasushi , Nakayama Keiichi I. , Iwamoto Itsuo 
Published: April 2014

AbstractAllergic inflammation is mediated by Th2 cell-derived cytokines, including IL-4, IL-5, and IL-13, and down-regulated by IFN-γ and IL-12. Tyk2 is a member of the Janus family of protein tyrosine kinases and is activated by a variety of cytokines: IFN-αβ, IL-6, IL-10, IL-12, and IL-13. In this study, we investigated the role of Tyk2 in the regulation of Ag-induced Th cell differentiation and Ag-induced allergic inflammation in the airways using Tyk2-deficient (Tyk2−/−) mice. When splenocytes were stimulated with antigenic peptide, IL-12-mediated Th1 cell differentiation was decreased, but IL-4-mediated Th2 cell differentiation was increased in Tyk2−/− mice. In vivo, Ag-specific IgE and IgG1 production was increased, but Ag-specific IgG2a production was decreased in Tyk2−/− mice as compared with those in control mice. In addition, Ag-induced eosinophil and CD4+ T cell recruitment, as well as the production of Th2 cytokines in the airways, was increased in Tyk2−/− mice. Adoptive transfer experiments revealed that CD4+ T cells were responsible for the enhanced Ag-induced eosinophil recruitment in Tyk2−/− mice. In contrast, although the level of IL-13 was increased in the airways of Tyk2−/− mice after Ag inhalation, the number of goblet cells, as well as Muc5ac mRNA expression, was decreased in Tyk2−/− mice. Together, these results indicate that Tyk2 plays a bilateral role in the regulation of allergic inflammation in the airways: Tyk2 plays a role in the down-regulation of Th2 cell-mediated Ab production and eosinophil recruitment in the airways by regulating Th1/Th2 balance toward Th1-type, while Tyk2 is necessary for the induction of IL-13-mediated goblet cell hyperplasia in the airways.
Cutting Edge: Proliferating Fibroblasts Respond to Collagenous C1q with Phosphorylation of p38 Mitogen-Activated Protein Kinase and Apoptotic Features
Authors: Bordin Sandra , Whitfield Douglas 
Published: April 2014

AbstractInteractions of C1q collagen tails with human fibroblasts induce G1 mitotic arrest. The hypothesis tested in this study is that the antiproliferative effect of C1q tails is mediated through activation of stress responsive pathway(s). Upon C1q treatment, proliferating fibroblasts were examined by immunoblotting with a panel of Abs to the mitogen-activated protein kinase (MAPK) superfamily. The cells selectively increased phosphorylation of p38 MAPK, upstream dual activator MAPK kinase 3/6, and downstream transcription factors activating transcription factor 2, ETS domain transcription factor 1, and C/EBP homologous protein in a time-dependent manner. Phosphorylations were mediated, in part, by ligation of surface C1q tail-binding calreticulin. These events correlated with the appearance of apoptotic nuclei and DNA fragmentation in the cultures, which increased with a time response curve. The apoptotic features were linked to p38 activities because the selective inhibitor SB203580 prevented both phosphorylation of the pathway and DNA fragmentation. Hence, p38 activation might provide a molecular basis for linking mitotic arrest and apoptosis of fibroblasts by C1q tails.
Inhibition of Metalloproteinase Cleavage Enhances the Cytotoxicity of Fas Ligand
Authors: Knox Pauline G. , Milner Anne E. , Green Nicky K. , Eliopoulos Aristides G. , Young Lawrence S. 
Published: April 2014

AbstractThe Fas ligand (FasL)/Fas receptor (CD95) pathway is an important mediator of apoptosis in the immune system and can also mediate cancer cell death. Soluble FasL (sFasL), shed from the membrane-bound form of the molecule by a putative metalloproteinase (MP), may function to locally regulate the activity of membrane-bound FasL. Using a replication-defective recombinant adenovirus-expressing FasL (RAdFasL), we identified a variable ability of different carcinoma cells to respond to FasL-induced cytotoxicity and to shed sFasL. Blockade of FasL cleavage with an MP inhibitor significantly enhanced RAdFasL-induced apoptosis suggesting that sFasL may antagonize the effect of membrane-bound FasL. In support of this concept, a recombinant adenovirus expressing a noncleavable form of FasL (RAdD4) was found to be a potent inducer of apoptosis even at very low virus doses. Our results highlight the therapeutic potential of noncleavable FasL as an antitumor agent and emphasize the important role of MP via the production of sFasL in regulating the response of the Fas pathway. Moreover, these findings have general implications for the therapeutic exploitation of TNF family ligands and for the possible impact of MP-based therapies on the normal physiology of Fas/TNF pathways.
Impaired Lymphopoiesis and Altered B Cell Subpopulations in Mice Overexpressing Lnk Adaptor Protein
Authors: Takaki Satoshi , Tezuka Yoshinari , Sauer Karsten , Kubo Chiyomi , Kwon Sang-Mo , Armstead Erin , Nakao Kazuki , Katsuki Motoya , Perlmutter Roger M. , Takatsu Kiyoshi 
Published: April 2014

Abstract
Lnk is an adaptor protein expressed primarily in lymphocytes and hemopoietic precursor cells. Marked expansion of B lineage cells occurs in lnk−/− mice, indicating that Lnk regulates B cell production by negatively controlling pro-B cell expansion. In addition, lnk−/− hemopoietic precursors have an advantage in repopulating the hemopoietic system of irradiated host animals. In this study, we show that Lnk overexpression results in impaired expansion of lymphoid precursor cells and altered mature B cell subpopulations. The representation of both B lineage and T lineage cells was reduced in transgenic mice overexpressing Lnk under the control of a lymphocyte-specific expression vector. Whereas the overall number of B and T cells was correlated with Lnk protein expression levels, marginal zone B cells in spleen and B1 cells in the peritoneal cavity were relatively resistant to Lnk overexpression. The C-terminal tyrosine residue, conserved among Lnk family adaptor proteins, was dispensable for the negative regulatory roles of Lnk in lymphocyte development. Our results illuminate the novel negative regulatory mechanism mediated by the Lnk adaptor protein in controlling lymphocyte production and function.
CD154 Plays a Central Role in Regulating Dendritic Cell Activation During Infections That Induce Th1 or Th2 Responses
Authors: Straw Amy D. , MacDonald Andrew S. , Denkers Eric Y. , Pearce Edward J. 
Published: April 2014

AbstractWe compared splenic DC activation during infection with either the Th2 response-inducing parasite Schistosoma mansoni or with the Th1 response-inducing parasite Toxoplasma gondii. CD8α+ DC from schistosome-infected mice exhibited a 2- to 3-fold increase in the expression of MHC class II, CD80, and CD40 (but not CD86) compared with DC from uninfected control animals, while CD8α− DC exhibited a 2- to 3-fold increase in the expression of MHC class II and CD80 and no alteration, compared with DC from uninfected mice, in the expression of CD86 or CD40. Intracellular staining revealed that DC did not produce IL-12 during infection with S. mansoni. In contrast, infection with T. gondii resulted in a more pronounced increase in the expression of activation-associated molecules (MHC class II, CD80, CD86, and CD40) on both CD8α− and CD8α+ splenic DC and promoted elevated IL-12 production by DC. Analysis of MHC class I and of additional costimulatory molecules (ICOSL, ICAM-1, OX40L, 4-1BBL, and B7-DC) revealed a generally similar pattern, with greater indication of activation in T. gondii-infected mice compared with S. mansoni-infected animals. Strikingly, the activation of DC observed during infection with either parasite was not apparent in DC from infected CD154−/− mice, indicating that CD40/CD154 interactions are essential for maintaining DC activation during infection regardless of whether the outcome is a Th1 or a Th2 response. However, the ability of this activation pathway to induce IL-12 production by DC is restrained in S. mansoni-infected, but not T. gondii-infected, mice by Ag-responsive CD11c− cells.
Mechanisms of Enhanced Macrophage-Mediated Prostaglandin E2 Production and Its Suppressive Role in Th1 Activation in Th2-Dominant BALB/c Mice
Authors: Kuroda Etsushi , Yamashita Uki 
Published: April 2014

AbstractPGE2 has been known to suppress Th1 responses. We studied the difference in strains of mice in PGE2 production by macrophages and its relation to Th1 activation. Macrophages from BALB/c mice produced greater amounts of PGE2 than those from any other strains of mice, including C57BL/6, after LPS stimulation. In accordance with the amount of PGE2 produced, macrophage-derived IL-12 and T cell-derived IFN-γ production were more strongly suppressed in BALB/c macrophages than in C57BL/6 macrophages. When macrophages were treated with indomethacin or EP4 antagonist, Th1 cytokines were more markedly increased in cells from BALB/c mice than in those from C57BL/6 mice. Although cyclooxygenase-2 was expressed similarly after LPS stimulation in these mouse strains, the release of arachidonic acid and the expression of type V secretory phospholipase A2 mRNA were greater in BALB/c macrophages. However, exogenous addition of arachidonic acid did not reverse the lower production of PGE2 by C57BL/6 macrophages. The expression of microsomal PGE synthase, a final enzyme of PGE2 synthesis, was also greater in BALB/c macrophages. These results indicate that the greater production of PGE2 by macrophages, which is regulated by secretory phospholipase A2 and microsomal PGE synthase but not by cyclooxygenase-2, is related to the suppression of Th1 cytokine production in BALB/c mice.
Nonmyelin-Specific T Cells Accelerate Development of Central Nervous System APC and Increase Susceptibility to Experimental Autoimmune Encephalomyelitis
Authors: Jones Richard E. , Kay Thomas , Keller Thomas , Bourdette Dennis 
Published: April 2014

AbstractPreviously we demonstrated that both myelin-specific and nonmyelin-specific rat T cells were capable of accelerating the development of transplanted rat BM-derived APC in the CNS of SCID C.B-17/scid (SCID) mice. This suggested that nonmyelin-specific T cells might be capable of increasing susceptibility to EAE by increasing the number and function of APC in the CNS before disease induction. To assess this possibility, we evaluated disease incidence, day of onset, duration, mean peak severity, cumulative disease index, and histopathology in the presence or absence of nonmyelin-specific T cells. The results demonstrate an association between T cell responses to nonmyelin Ags, accelerated development of BM-derived CNS APC before disease induction, and heightened susceptibility to CNS inflammation mediated by myelin-specific T cells. This suggests that T cell responses to nonmyelin Ags can potentiate CNS inflammation by elevating the functional presence of CNS APC.
IL-6 and Matrix Metalloproteinase-1 Are Regulated by the Cyclin-Dependent Kinase Inhibitor p21 in Synovial Fibroblasts
Authors: Perlman Harris , Bradley Kathleen , Liu Hongtao , Cole Shawn , Shamiyeh Eli , Smith Roy C. , Walsh Kenneth , Fiore Stefano , Koch Alisa E. , Firestein Gary S. , Haines G. Kenneth , Pope Richard M. 
Published: April 2014

AbstractDuring the pathogenesis of rheumatoid arthritis (RA), the synovial fibroblasts increase in number and produce proinflammatory cytokines and matrix metalloproteinases (MMPs) that function to promote inflammation and joint destruction. Recent investigations have suggested that cell cycle activity and inflammation may be linked. However, little is known about the mechanisms responsible for the coordinate regulation of proliferation and the expression of proinflammatory molecules in RA synovial fibroblasts. Here, we demonstrate a 50 ± 10% decrease in the expression of p21, a cell cycle inhibitor, in the synovial fibroblast population from RA compared with osteoarthritis (OA) synovial tissue. Moreover, p21 positivity in the synovial fibroblasts inversely correlates with medium synovial lining thickness (r = −0.76; p &lt; 0.02). The expression of p21 is also reduced in isolated RA synovial fibroblasts compared with OA synovial fibroblasts. Adenovirus-mediated delivery of p21 (Ad-p21) arrests both RA and OA synovial fibroblasts in the G0/G1 phase of the cell cycle without inducing cytotoxicity. However, the spontaneous production of IL-6 and MMP-1 is suppressed only in the Ad-p21-infected RA synovial fibroblasts, indicating a novel role for p21 in RA. Analyses of p21-deficient mouse synovial fibroblasts reveal a 100-fold increase in IL-6 protein and enhance IL-6 and MMP-3 mRNA. Restoration of p21, but not overexpression of Rb, which also induces G0/G1 cell cycle arrest, decreases IL-6 synthesis in p21-null synovial fibroblasts. Furthermore, in RA synovial fibroblasts the ectopic expression of p21 reduces activation of the AP-1 transcription factor. Additionally, p21-null synovial fibroblasts display enhanced activation of AP-1 compared with wild-type synovial fibroblasts. These data suggest that alterations in p21 expression may activate AP-1 leading to enhanced proinflammatory cytokine and MMP production and development of autoimmune disease.
The GTP-Binding Domain of Class II Transactivator Regulates Its Nuclear Export
Authors: Raval Aparna , Weissman Jocelyn D. , Howcroft T. Kevin , Singer Dinah S. 
Published: April 2014

Abstract
The transcriptional coactivator class II transactivator (CIITA), although predominantly localized in the nucleus, is also present in the cytoplasm. The subcellular distribution of CIITA is actively regulated by the opposing actions of nuclear export and import. In this study, we show that nuclear export is negatively regulated by the GTP-binding domain (GBD; aa 421–561) of CIITA: mutation or deletion of the GBD markedly increased export of CIITA from the nucleus. Remarkably, a CIITA GBD mutant binds CRM1/exportin significantly better than does wild-type CIITA, leading to the conclusion that GTP is a negative regulator of CIITA nuclear export. We also report that, in addition to the previously characterized N- and C-terminal nuclear localization signal elements, there is an additional N-terminal nuclear localization activity, present between aa 209 and 222, which overlaps the proline/serine/threonine-rich domain of CIITA. Thus, fine-tuning of the nucleocytoplasmic distribution of coactivator proteins involved in transcription is an active and dynamic process that defines a novel mechanism for controlling gene regulation.
Identification of IFN Regulatory Factor-1 Binding Site in IL-12 p40 Gene Promoter
Authors: Maruyama Saho , Sumita Kohsuke , Shen Hua , Kanoh Makoto , Xu Xin , Sato Mitsuharu , Matsumoto Masahito , Shinomiya Hiroto , Asano Yoshihiro 
Published: April 2014

AbstractIL-12 is a heterodimer composed of p40 and p35 and is a key cytokine that functions to protect the host from viral and microbial infections. IL-12 links the innate immune system with the acquired immune system during infection, and induces differentiation of type 1 T cells that play an important role in the eradication of microbes. The induction of the IL-12 p40 gene is regulated by NF-κB in the presence of IFN-γ. IFN-γ induces IFN regulatory factor-1 (IRF-1), which in turn induces the transcription of the IL-12 p40 gene. However, the IRF-1 binding site in the promoter region of the IL-12 p40 gene has not yet been formally determined. In the present study, we demonstrated that IRF-1 directly binds to the IL-12 p40 gene promoter and identified its binding site. The IRF-1 binding site in the promoter region of the IL-12 p40 gene is shown to be in the −72 to −58 area of the 5′-upstream region. The −63 to −61 position is the critical site within this region for the binding of IRF-1 to the IL-12 p40 gene promoter. While IFN-γ must be present for IL-12 p40 gene induction, the p35 gene is strongly induced by LPS, even in the absence of IFN-γ, and therefore the induction of the p35 gene is IRF-1 independent.
Cutting Edge: The G-U Mismatch Glycosylase Methyl-CpG Binding Domain 4 Is Dispensable for Somatic Hypermutation and Class Switch Recombination
Authors: Bardwell Philip D. , Martin Alberto , Wong Edmund , Li Ziqiang , Edelmann Winfried , Scharff Matthew D. 
Published: April 2014

Abstract
Affinity maturation of the humoral response is accomplished by somatic hypermutation and class switch recombination (CSR) of Ig genes. Activation-induced cytidine deaminase likely initiates these processes by deamination of cytidines in the V and switch regions of Ig genes. This activity is expected to produce G-U mismatches that can be substrates for MutS homolog 2/MutS homolog 6 heterodimers and for uracil DNA glycosylase. However, G-T and G-U mismatches are also substrates of the methyl-CpG binding domain 4 (Mbd4) glycosylase. To determine whether Mbd4 functions downstream of activation-induced cytidine deaminase activity, we examined somatic hypermutation and CSR in Mbd4−/− mice. In this study, we report that CSR, as analyzed by an in vitro switch assay and by in vivo immunizations, is unaffected in Mbd4−/− mice. In addition, the hypermutated JH2 to JH4 region in Peyer’s patch B cells showed no effects as a result of Mbd4 deficiency. These data indicate that the Mbd4 glycosylase does not significantly contribute to mechanisms of Ab diversification.
Targeting Apoptotic Tumor Cells to FcγR Provides Efficient and Versatile Vaccination Against Tumors by Dendritic Cells
Authors: Akiyama Kenichi , Ebihara Shin , Yada Ayumi , Matsumura Kimio , Aiba Setsuya , Nukiwa Toshihiro , Takai Toshiyuki 
Published: April 2014

Abstract
Dendritic cells (DCs) loaded with tumor-associated Ags (TAAs) act as potent adjuvant that initiates antitumor immune responses in vivo. However, TAA-based DC vaccination requires prior identification of TAAs. Apoptotic tumor cells (ATCs) can be an excellent source for DC loading because their potential uncharacterized Ags would be efficiently presented to T cells without any prior characterization and isolation of these Ags. However, ATCs alone are considered to be inefficient for activating antitumor immunity, possibly because of their inability to induce DC maturation. In this study, the aim was to enhance antitumor immune response by taking advantage of ATCs that have been opsonized with IgG (ATC-immune complexes, ATC-ICs) so as to target them to FcR for IgG (FcγRs) on DCs. It was found that when compared with ATCs, ATC-ICs were efficiently internalized by DCs via FcγRs, and this process induced maturation of DCs, which was more efficient than that of ATCs. Importantly, ATC-IC loading was shown to be more efficient than ATCs alone in its capacity for inducing antitumor immunity in vivo, in terms of cytotoxic T cell induction and tumor rejection. These results show that using ATC-ICs may overcome the limitations and may enhance the immune response of current ATC-based DC vaccination therapy.
Th1 and Th2 Pancreatic Inflammation Differentially Affects Homing of Islet-Reactive CD4 Cells in Nonobese Diabetic Mice
Authors: Hill Natasha J. , Van Gunst Kurt , Sarvetnick Nora 
Published: April 2014

Abstract
The control of lymphocyte recruitment to the site of inflammation is an important component determining the pathogenicity of an autoimmune response. Progression from insulitis to diabetes in the nonobese diabetic mouse is typically associated with Th1 pancreatic inflammation, whereas Th2 inflammation can seemingly be controlled indefinitely. We show that a Th1 (IFN-γ) pancreatic environment greatly accelerates the recruitment of adoptively transferred islet-specific CD4 T cells to the islets and also accelerates the onset of diabetes. The increased number of islet-reactive T cells in the pancreas does not result from increased proliferation or a decreased rate of apoptosis; instead, it appears to be caused by a greatly facilitated rate of entry to the pancreas. In contrast, a Th2 (IL-4) pancreatic environment does act to enhance Ag-specific proliferation and decrease the rate of apoptosis in islet-specific CD4 T cells. Nonpathogenic/regulatory cells are not preferentially expanded by the presence of IL-4. Increased recruitment to the islets was also observed in the presence of IL-4, but to a lesser extent than in the presence of IFN-γ, and this lesser increase in the rate of recruitment did not accelerate diabetes onset within the time period examined. Therefore, the production of Th1 cytokines by initial islet-infiltrating cells may cause a greater increase than Th2 cytokines in the rate of recruitment of activated T cells. This difference in rate of recruitment may be critical in determining whether the initial infiltrate proceeds to diabetes or whether a steady state insulitis develops that can be maintained.
CD4+CD25− T Cells in Aged Mice Are Hyporesponsive and Exhibit Suppressive Activity
Authors: Shimizu Jun , Moriizumi Eiko 
Published: April 2014

Abstract
Studies on humans and rodents have established that functional deterioration of CD4 T cells occurs with aging. We report in this study that ∼70% of CD4+CD25− T cell preparations from individual 24-mo-old mice are hyporesponsive to in vitro stimulation with anti-CD3 Ab. The remaining 30% of CD4+CD25− T cell preparations showing the intermediate or normal responsiveness in the primary stimulation also exhibit the hyporesponsive properties after primary stimulation. Both of these hyporesponsive aged CD4+CD25− T cells could inhibit the proliferation of cocultured CD4+CD25− T cells from young mice, like CD4+CD25+ T cells, which have recently been demonstrated as an immune regulator in young mice. Another experiment revealed that hyporesponsive aged CD4+CD25− T cells arrest the cell division of cocultured young CD4+CD25− T cells. The suppressive activity observed in aged CD4+CD25− T cells is aging-dependent, not mediated by humoral factors, cell-contact dependent, and broken by the addition of IL-2 or anti-GITR Ab, but not by anti-CTLA-4 Ab. These studies show that aging not only leads to a decline in the ability to mount CD4+CD25− T cell responses, but at the same time, also renders these aged CD4+CD25− T cells suppressive.
Lack of the Transcriptional Coactivator OBF-1 Prevents the Development of Systemic Lupus Erythematosus-Like Phenotypes in Aiolos Mutant Mice
Authors: Sun Jian , Matthias Gabriele , Mihatsch Michael J. , Georgopoulos Katia , Matthias Patrick 
Published: April 2014

Abstract
Here we show that mice lacking the zinc finger transcription factor Aiolos develop the symptoms of human systemic lupus erythematosus (SLE), which is characterized by the production of anti-dsDNA Ab and immune complex-mediated glomerulonephritis. This finding indicates that normal Aiolos function is necessary to maintain immune homeostasis and suppress the development of systemic autoimmune disease and implicates Aiolos as a possible candidate gene for SLE. Interestingly, Aiolos-null mice can no longer mount autoimmune reactions and completely fail to develop SLE when they are deficient for the B cell-specific transcription coactivator OBF-1. The lack of OBF-1 reverses several Aiolos mutant mouse phenotypes, such as B cell hyperproliferation, high expression of activation marker on B cells, and spontaneous germinal center formation. Unexpectedly, B cell development at the immature B cell stage is severely impaired in the bone marrow of Aiolos/OBF-1 double-deficient mice, demonstrating the key role of these factors in the transition from pre-B to immature B cells. Our results indicate that B cells play a crucial role in the development of SLE in Aiolos mutant mice and might be useful for the strategy of SLE treatment.