bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneity of Dendritic Cells in the Mouse Liver: Identification and Characterization of Four Distinct Populations
Authors: Lian Zhe-Xiong , Okada Tomoyuki , He Xiao-Song , Kita Hiroto , Liu Yong-Jun , Ansari Aftab A. , Kikuchi Kentaro , Ikehara Susumu , Gershwin M. Eric 
Published: April 2014

Abstract
Liver dendritic cells (DC) are believed to play important roles in liver immunity, autoimmunity, and in the regulation of hepatic allograft acceptance. However, limited information is available on the phenotypes and functions of DC in the liver. To address this issue, we isolated DC from murine liver using procedures that do not involve collagenase, and characterized the freshly isolated DC population that had not been subjected to in vitro expansion. Thence, based on the expression of CD4, B220, and CD11b, four subsets or groups of hepatic NK1.1−CD11c+ DC were identified with the following phenotypes: B220+CD4+, B220+CD4−, B220−CD11b+, and B220−CD11b−. Each subset was further characterized both phenotypically and functionally. In addition to unique phenotypic expression, each subset displayed different allostimulation capability in mixed lymphocyte reaction assays. All four groups developed DC morphology following in vitro culture with activation agents and synthesized distinct patterns of cytokines in response to different stimuli. Taken together, our results suggest that groups I and II are IFN-α-producing plasmacytoid DC, group III cells are myeloid-related DC, while group IV is a heterogenous population containing both myeloid- and lymphoid-related DC. Our results demonstrate the highly heterogeneous nature of hepatic DC, which is in agreement with the unique requirements for APC in the complex liver environment.
Expression of Complement 3 and Complement 5 in Newt Limb and Lens Regeneration
Authors: Kimura Yuko , Madhavan Mayur , Call Mindy K. , Santiago William , Tsonis Panagiotis A. , Lambris John D. , Del Rio-Tsonis Katia 
Published: April 2014

Abstract
Some urodele amphibians possess the capacity to regenerate their body parts, including the limbs and the lens of the eye. The molecular pathway(s) involved in urodele regeneration are largely unknown. We have previously suggested that complement may participate in limb regeneration in axolotls. To further define its role in the regenerative process, we have examined the pattern of distribution and spatiotemporal expression of two key components, C3 and C5, during limb and lens regeneration in the newt Notophthalmus viridescens. First, we have cloned newt cDNAs encoding C3 and C5 and have generated Abs specifically recognizing these molecules. Using these newt-specific probes, we have found by in situ hybridization and immunohistochemical analysis that these molecules are expressed during both limb and lens regeneration, but not in the normal limb and lens. The C3 and C5 proteins were expressed in a complementary fashion during limb regeneration, with C3 being expressed mainly in the blastema and C5 exclusively in the wound epithelium. Similarly, during the process of lens regeneration, C3 was detected in the iris and cornea, while C5 was present in the regenerating lens vesicle as well as the cornea. The distinct expression profile of complement proteins in regenerative tissues of the urodele lens and limb supports a nonimmunologic function of complement in tissue regeneration and constitutes the first systematic effort to dissect its involvement in regenerative processes of lower vertebrate species.
Growth Factor Independence-1B Expression Leads to Defects in T Cell Activation, IL-7 Receptor α Expression, and T Cell Lineage Commitment
Authors: Doan Loretta L. , Kitay Mary Kate , Yu Qing , Singer Alfred , Herblot Sabine , Hoang Trang , Bear Susan E. , Morse Herbert C. , Tsichlis Philip N. , Grimes H. Leighton 
Published: April 2014

Abstract
T cell differentiation in the thymus is dependent upon signaling through the TCR and is characterized by the resulting changes in expression patterns of CD4 and CD8 surface coreceptor molecules. Although recent studies have characterized the effects of proximal TCR signaling on T cell differentiation, the downstream integration of these signals remains largely unknown. The growth factor independence-1 (GFI1) and GFI1B transcriptional repressors may regulate cytokine signaling pathways to affect lymphocyte growth and survival. In this study, we show that Gfi1 expression is induced upon induction of the T cell program. Gfi1B expression is low and dynamic during T cell development, but is terminated in mature thymocytes. Transgenic expression of GFI1 and GFI1B in T cells allowed us to determine the functional consequences of constitutive expression. GFI1 potentiates response to TCR stimulation and IL-2, whereas GFI1B-transgenic T cells are defective in T cell activation. Moreover, GFI1B-transgenic thymocytes display reduced expression of the late-activation marker IL-7Rα, and a decrease in CD4−8+ single-positive T cells that can be mitigated by transgenic expression of BCL2 or GFI1. These data show that GFI1 and GFI1B are functionally unique, and implicate a role for GFI1 in the integration of activation and survival signals.
Inhibition of TCR-Induced CD8 T Cell Death by IL-12: Regulation of Fas Ligand and Cellular FLIP Expression and Caspase Activation by IL-12
Authors: Lee Seung Woo , Park Yunji , Yoo Jae Kwang , Choi So Young , Sung Young Chul 
Published: April 2014

Abstract
In this study we demonstrate the anti-apoptotic effect of IL-12 and its underlying mechanism in CD8 T cells. The prolonged stimulation of CD8 T cells with anti-CD3 alone caused apoptosis mediated by Fas and the caspase signaling pathway. However, costimulation with IL-12 significantly prevented anti-CD3-induced apoptosis of CD8 T cells. IL-12 decreased the number of Fas ligand-positive CD8 T cells and inhibited the activation of caspase-8 and caspase-3. In addition, IL-12 up-regulated cellular FLIPs but not Bcl-2 family proteins or cellular inhibitor of apoptosis proteins. These data suggest that IL-12 provides survival signals to CD8 T cells by down-regulating Fas ligand and up-regulating cellular FLIPs, followed by inhibiting caspase activation, which implies a role for IL-12 in peripheral responses of CD8 T cells in vivo.
IL-13 Is Necessary, Not Simply Sufficient, for Epicutaneously Induced Th2 Responses to Soluble Protein Antigen
Authors: Herrick Christina A. , Xu Lan , McKenzie Andrew N. J. , Tigelaar Robert E. , Bottomly Kim 
Published: April 2014

AbstractTh2 responses are clearly involved in the pathogenesis of atopic disease. Thus, understanding the factors responsible for Th2 sensitization at sites of allergen exposure, such as airway and skin, is crucial for directing therapeutic or preventive strategies. Contrary to other models of Th2 sensitization to proteins, we have reported that Th2 responses induced by epicutaneous exposure to OVA are IL-4 independent. Combined deficiency of both IL-4 and IL-13 signaling did prevent Th2 generation, suggesting that IL-13 was mediating these IL-4-independent responses. It was not clear, however, whether IL-13 was simply replacing the need for IL-4 in genetically deficient mice or if IL-13 played a unique role. In the present study, we show that Th2 responses induced by epicutaneous OVA exposure (including lung inflammatory responses after inhaled Ag challenge, OVA-specific IgG1, and draining lymph node IL-5 production) are impaired in IL-13-deficient (IL-13−/−) mice compared with wild type. In contrast, i.p. sensitization of IL-13−/− mice resulted in responses equivalent to wild type. Generation of contact hypersensitivity to dinitrofluorobenzene, which involves Th1 and CD8+ effector cells, was also intact in IL-13−/− mice. Taken together, the data indicate that IL-13 is the major inducer of Th2 generation in the cutaneous microenvironment, being required independently of IL-4. This fact, in combination with the known abundance of IL-13 in atopic dermatitis skin lesions, emphasizes the potentially important role of the skin as a site for Th2 sensitization to environmental allergens, particularly in atopic individuals.
CD4+CD25− T Cells That Express Latency-Associated Peptide on the Surface Suppress CD4+CD45RBhigh-Induced Colitis by a TGF-β-Dependent Mechanism
Authors: Oida Takatoku , Zhang Xingmin , Goto Masao , Hachimura Satoshi , Totsuka Mamoru , Kaminogawa Shuichi , Weiner Howard L. 
Published: April 2014

Abstract
Murine CD4+CD25+ regulatory cells have been reported to express latency-associated peptide (LAP) and TGF-β on the surface after activation, and exert regulatory function by the membrane-bound TGF-β in vitro. We have now found that a small population of CD4+ T cells, both CD25+ and CD25−, can be stained with a goat anti-LAP polyclonal Ab without being stimulated. Virtually all these LAP+ cells are also positive for thrombospondin, which has the ability to convert latent TGF-β to the active form. In the CD4+CD45RBhigh-induced colitis model of SCID mice, regulatory activity was exhibited not only by CD25+LAP+ and CD25+LAP− cells, but also by CD25−LAP+ cells. CD4+CD25−LAP+ T cells were part of the CD45RBlow cell fraction. CD4+CD25−LAP−CD45RBlow cells had minimal, if any, regulatory activity in the colitis model. The regulatory function of CD25−LAP+ cells was abrogated in vivo by anti-TGF-β mAb. These results identify a new TGF-β-dependent regulatory CD4+ T cell phenotype that is CD25− and LAP+.
Role of the Polymeric Ig Receptor in Mucosal B Cell Homeostasis
Authors: Uren Tania K. , Johansen Finn-Eirik , Wijburg Odilia L. C. , Koentgen Frank , Brandtzaeg Per , Strugnell Richard A. 
Published: April 2014

AbstractSecretory IgA (SIgA) is the most characteristic component of the mucosal immune system and has long been considered the major protective factor that prevents pathogens from invading hosts through the mucosae. Recent studies, however, have suggested that complete immunity against a range of mucosal bacterial and viral pathogens can be achieved in the absence of IgA. Therefore, to further dissect the role of SIgA, we generated mice deficient in the polymeric Ig receptor (pIgR−/− mice). As a result of an inability to transport dimeric IgA to the secretions, pIgR−/− mice are deficient in SIgA and accumulate circulating dimeric IgA, with serum levels 100-fold greater than those observed in normal mice. Examination of lamina propria mononuclear cells showed that pIgR−/− mice had ∼3 times as many IgA-secreting cells as C57BL/6 mice. Further analysis showed that these cells displayed the differentiated IgA+ B220− phenotype and accounted for a 2-fold increase in the number of lamina propria blast cells in the pIgR−/− mice. Subsequent experiments showed that OVA-specific CD4+ T cell expansion following OVA feeding was not elevated in pIgR−/− mice. Furthermore, no differences in CD8+ T cell tolerance or induction of influenza virus-specific CD8+ T cells were detected in pIgR−/− mice compared with controls. Therefore, while SIgA is clearly involved in maintaining some parameters of mucosal homeostasis in the intestine, the mechanisms associated with its barrier function and the clinical consequences of its deficiency are yet to be identified.
Unique Monoclonal Antibodies Define Expression of FcγRI on Macrophages and Mast Cell Lines and Demonstrate Heterogeneity Among Subcutaneous and Other Dendritic Cells
Authors: Tan Peck S. , Gavin Amanda L. , Barnes Nadine , Sears Duane W. , Vremec David , Shortman Ken , Amigorena Sebastian , Mottram Patricia L. , Hogarth P. Mark 
Published: April 2014

AbstractThe mouse FcγRI is one of the most fundamentally important FcRs. It participates in different stages of immunity, being a low affinity receptor for T-independent IgG3 and yet a high affinity receptor for IgG2a, the product of a Th1 immune response. However, analysis of this receptor has been difficult due largely to the failure to generate specific Abs to this FcR. We have made use of the polymorphic differences between BALB/c and NOD/Lt mice to generate mAb specific for the FcγRI of BALB/c and the majority of in-bred mouse strains. Three different mAb were obtained that detected FcγRI encoded by the more common Fcgr1a and Fcgr1b alleles, and although they identified different epitopes, none inhibited the binding of IgG to FcγRI. When bound to FcγRI, these mAb induced calcium mobilization upon cross-linking. Several novel observations were made of the cellular distribution of FcγRI. Resting and IFN-γ-induced macrophages expressed FcγRI as well as mast cell lines. Both bone marrow-derived and freshly isolated dendritic cells from spleen and lymph nodes expressed FcγRI. A class of DC, uniquely found in s.c. lymph nodes, expressed the highest level of FcγRI and also high levels of MHC class II, DEC205, CD40, and CD86, with a low level of CD8α, corresponding to the phenotype for Langerhans-derived DC, which are highly active in Ag processing. Thus, in addition to any role in effector functions, FcγRI on APC may act as a link between innate and adaptive immunities by binding and mediating the uptake of T-independent immune complexes for presentation, thereby assisting in the development of T-dependent immune responses.
Bone Morphogenetic Protein-7 Inhibits Constitutive and Interleukin-1β-Induced Monocyte Chemoattractant Protein-1 Expression in Human Mesangial Cells: Role for JNK/AP-1 Pathway
Authors: Lee Myung-Ja , Yang Chul Woo , Jin Dong Chan , Chang Yoon Sik , Bang Byung Kee , Kim Yong-Soo 
Published: April 2014

Abstract
Bone morphogenetic protein-7 (BMP-7), which belongs to the TGF-β superfamily, has been shown to reduce macrophage infiltration and tissue injury in animal models of inflammatory renal disease. To explore the mechanism involved in the anti-inflammatory effect, we investigated the effect of BMP-7 on monocyte chemoattractant protein-1 (MCP-1) expression in cultured human mesangial cells. BMP- 7 significantly inhibited constitutive and IL-1β-induced MCP-1 protein production and MCP-1 mRNA expression by mesangial cells in a time- and concentration-dependent manner. BMP-7 also inhibited IL-1β-induced monocyte chemotactic activity released from the mesangial cells. We examined the role of transcription factors NF-κB and AP-1 in BMP-7 inhibition of IL-1β-induced MCP-1 expression. IL-1β increased NF-κB and AP-1 activity and both transcription factors mediated IL-1β-induced MCP-1 expression in mesangial cells. BMP-7 inhibited IL-1β-induced AP-1 activity in a concentration-dependent manner. In contrast, IL-1β-induced NF-κB activity and IκBα degradation were not affected by BMP-7. Furthermore, IL-1β-induced phosphorylation of c-Jun N-terminal kinase was inhibited by BMP-7. These data suggest that BMP-7 inhibits constitutive and IL-1β-induced MCP-1 expression in human mesangial cells partly by inhibiting c-Jun N-terminal kinase activity and subsequent AP-1 activity, and provide new insight into the therapeutic potential of BMP-7 in the inflammatory renal diseases.
CD8-Independent Tumor Cell Recognition Is a Property of the T Cell Receptor and Not the T Cell
Authors: Roszkowski Jeffrey J. , Yu David C. , Rubinstein Mark P. , McKee Mark D. , Cole David J. , Nishimura Michael I. 
Published: April 2014

AbstractThe CD8 coreceptor enhances T cell function by stabilizing the TCR/peptide/MHC complex and/or increasing T cell avidity via interactions with the intracellular kinases Lck and LAT. We previously reported a CD4+ T cell (TIL 1383I), which recognizes the tumor-associated Ag tyrosinase in the context of HLA-A2. To determine whether CD8 independent tumor cell recognition is a property of the TCR, we used retroviral transduction to express the TIL 1383I TCR in the CD8− murine lymphoma, 58 α−/β−. Immunofluorescent staining of TCR-transduced cells with human TCR Vβ subfamily-specific and mouse CD3-specific Abs confirmed surface expression of the transferred TCR and coexpression of mouse CD3. Transduced effector cells secreted significant amounts of IL-2 following Ag presentation by tyrosinase peptide-pulsed T2 cells as well as stimulation with HLA-A2+ melanoma lines compared with T2 cells alone or HLA-A2− melanoma cells. Further analysis of TCR-transduced clones demonstrated a correlation between T cell avidity and cell surface expression of the TCR. Therefore, the TIL 1383I TCR has sufficient affinity to mediate recognition of the physiologic levels of Ag expressed by tumor cells in the absence of CD8 expression.
Activation of TGF-β by Leishmania chagasi: Importance for Parasite Survival in Macrophages
Authors: Gantt Kira R. , Schultz-Cherry Stacey , Rodriguez Nilda , Jeronimo Selma M. B. , Nascimento Eliana T. , Goldman Todd L. , Recker Thomas J. , Miller Melissa A. , Wilson Mary E. 
Published: April 2014

Abstract
TGF-β is a potent regulatory cytokine that suppresses expression of inducible NO synthase and IFN-γ, and suppresses Th1 and Th2 cell development. We examined whether functionally active TGF-β is present in the local environment surrounding the invading protozoan Leishmania chagasi. Our prior data showed that TGF-β levels are significantly increased in L. chagasi-infected mice. In the current study, we found TGF-β was also abundant in bone marrows of humans with acute visceral leishmaniasis but not in those of uninfected controls. Furthermore, L. chagasi infection caused an increase in biologically active TGF-β in human macrophage cultures without changing the total TGF-β. Therefore, we investigated the means through which leishmania could augment activated but not total TGF-β. Incubation of latent TGF-β with Leishmania sp. promastigotes caused active TGF-β to be released from the latent complex. In contrast, the nonpathogenic protozoan Crithidia fasciculata could not activate TGF-β. TGF-β activation by leishmania was prevented by inhibitors of cysteine proteases and by the specific cathepsin B inhibitor CA074. Physiologic concentrations of TGF-β inhibited killing of intracellular L. chagasi in macrophages, although the phagocytosis-induced respiratory burst remained intact. In contrast, supraphysiologic concentrations of TGF-β had no effect on parasite survival. We hypothesize that the combined effect of abundant TGF-β stores at extracellular sites during infection, and the ability of the parasite to activate TGF-β in its local environment, leads to high levels of active TGF-β in the vicinity of the infected macrophage. Locally activated TGF-β could, in turn, enhance parasite survival through its effects on innate and adaptive immune responses.
HIV-1 Tat-Mediated Apoptosis in Human Brain Microvascular Endothelial Cells
Authors: Kim Tae-Aug , Avraham Hava Karsenty , Koh Young-Ho , Jiang Shuxian , Park In-Woo , Avraham Shalom 
Published: April 2014

AbstractThe integrity of the blood-brain barrier (BBB) is critical for normal brain function. Neuropathological abnormalities in AIDS patients have been associated with perivascular HIV-infected macrophages, gliosis, and abnormalities in the permeability of the BBB. The processes by which HIV causes these pathological conditions are not well understood. To characterize the mechanism by which HIV-1 Tat protein modulates human brain microvascular endothelial cell (HBMEC) functions, we studied the effects of HIV-1 Tat in modulating HBMEC apoptosis and permeability. Treatment of HBMEC with HIV-1 Tat led to Flk-1/KDR and Flt-4 receptor activation and the release of NO. The protein levels of endothelial NO synthase (NOS) and inducible NOS were increased by HIV-1 Tat stimulation. Importantly, HIV-1 Tat caused apoptosis of HBMEC, as evidenced by changes in the cleavage of poly(A)DP-ribose polymerase, DNA laddering, and incorporation of fluorescein into the nicked chromosomal DNA (TUNEL assay). HIV-1 Tat-mediated apoptosis in HBMEC was significantly inhibited in the presence of N-nitro-l-arginine methyl ester (an inhibitor of NOS) and wortmannin (a phosphoinositol 3-kinase inhibitor). Furthermore, HIV-1 Tat treatment significantly increased HBMEC permeability, and pretreatment with both N-nitro-l-arginine methyl ester and wortmannin inhibited the Tat-induced permeability. Taken together, these results indicate that dysregulated production of NO by HIV-1 Tat plays a pivotal role in brain endothelial injury, resulting in the irreversible loss of BBB integrity, which may lead to enhanced infiltration of virus-carrying cells across the BBB.
Essential Role of Phosphoinositide 3-Kinase δ in Neutrophil Directional Movement
Authors: Sadhu Chanchal , Masinovsky Boris , Dick Ken , Sowell C. Gregory , Staunton Donald E. 
Published: April 2014

Abstract
Neutrophil chemotaxis is a critical component of the innate immune response. Neutrophils can sense an extremely shallow gradient of chemoattractants and produce relatively robust chemotactic behavior. This directional migration requires cell polarization with actin polymerization occurring predominantly in the leading edge. Synthesis of phosphatidylinositol (3,4,5) trisphosphate (PIP3) by phosphoinositide 3-kinase (PI3K) contributes to asymmetric F-actin synthesis and cell polarization during neutrophil chemotaxis. To determine the contribution of the hemopoietic cell-restricted PI3Kδ in neutrophil chemotaxis, we have developed a potent and selective PI3Kδ inhibitor, IC87114. IC87114 inhibited polarized morphology of neutrophils, fMLP-stimulated PIP3 production and chemotaxis. Tracking analysis of IC87114-treated neutrophils indicated that PI3Kδ activity was required for the directional component of chemotaxis, but not for random movement. Inhibition of PI3Kδ, however, did not block F-actin synthesis or neutrophil adhesion. These results demonstrate that PI3Kδ can play a selective role in the amplification of PIP3 levels that lead to neutrophil polarization and directional migration.
IL-17 Promotes Bone Erosion in Murine Collagen-Induced Arthritis Through Loss of the Receptor Activator of NF-κB Ligand/Osteoprotegerin Balance
Authors: Lubberts Erik , van den Bersselaar Liduine , Oppers-Walgreen Birgitte , Schwarzenberger Paul , Coenen-de Roo Christina J. J. , Kolls Jay K. , Joosten Leo A. B. , van den Berg Wim B. 
Published: April 2014

Abstract
IL-17 is a T cell-derived proinflammatory cytokine in experimental arthritis and is a stimulator of osteoclastogenesis in vitro. In this study, we report the effects of IL-17 overexpression (AdIL-17) in the knee joint of type II collagen-immunized mice on bone erosion and synovial receptor activator of NF-κB ligand (RANKL)/receptor activator of NF-κB/osteoprotegerin (OPG) expression. Local IL-17 promoted osteoclastic bone destruction, which was accompanied with marked tartrate-resistant acid phosphatase activity at sites of bone erosion in cortical, subchondral, and trabecular bone. Accelerated expression of RANKL and its receptor, receptor activator of NF-κB, was found in the synovial infiltrate and at sites of focal bone erosion, using specific immunohistochemistry. Interestingly, AdIL-17 not only enhanced RANKL expression but also strongly up-regulated the RANKL/OPG ratio in the synovium. Comparison of arthritic mice from the AdIL-17 collagen-induced arthritis group with full-blown collagen-arthritic mice having similar clinical scores for joint inflammation revealed lower RANKL/OPG ratio and tartrate-resistant acid phosphatase activity in the latter group. Interestingly, systemic OPG treatment prevented joint damage induced by local AdIL-17 gene transfer in type II collagen-immunized mice. These findings suggest T cell IL-17 to be an important inducer of RANKL expression leading to loss of the RANKL/OPG balance, stimulating osteoclastogenesis and bone erosion in arthritis.