bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcription Factor Early Growth Response 3 Is Associated with the TGF-β1 Expression and the Regulatory Activity of CD4-Positive T Cells In Vivo
Authors: Sumitomo Shuji , Fujio Keishi , Okamura Tomohisa , Morita Kaoru , Ishigaki Kazuyoshi , Suzukawa Keigo , Kanaya Kaori , Kondo Kenji , Yamasoba Tatsuya , Furukawa Asayo , Kitahara Noburou , Shoda Hirofumi , Shibuya Mihoko , Okamoto Akiko , Yamamoto Kazuhiko 
Published: August 2013

AbstractTGF-β1 is an important anti-inflammatory cytokine, and several regulatory T cell (Treg) subsets including CD4+CD25+Foxp3+ Tregs and Th3 cells have been reported to exert regulatory activity via the production of TGF-β1. However, it has not yet been elucidated which transcription factor is involved in TGF-β1 transcription. Early growth response 3 (Egr-3) is a zinc-finger transcription factor that creates and maintains T cell anergy. In this study, we found that Egr-3 induces the expression of TGF-β1 in both murine and human CD4+ T cells. Egr-3 overexpression in murine CD4+ T cells induced the production of TGF-β1 and enhanced the phosphorylation of STAT3, which is associated with TGF-β1 transcription. Moreover, Egr-3 conferred Ag-specific regulatory activity on murine CD4+ T cells. In collagen-induced arthritis and delayed-type hypersensitivity model mice, Egr-3–transduced CD4+ T cells exhibited significant regulatory activity in vivo. In particular, the suppression of delayed-type hypersensitivity depended on TGF-β1. In human tonsils, we found that CD4+CD25−CD45RO−lymphocyte activation gene 3 (LAG3)− T cells express membrane-bound TGF-β1 in an EGR3-dependent manner. Gene-expression analysis revealed that CD4+CD25−CD45RO−LAG3− T cells are quite different from conventional CD4+CD25+Foxp3+ Tregs. Intriguingly, the CD4+CD25−CD45RO−LAG3− T cells suppressed graft-versus-host disease in immunodeficient mice transplanted with human PBMCs. Our results suggest that Egr-3 is a transcription factor associated with TGF-β1 expression and in vivo regulatory activity in both mice and humans.
Histones Activate the NLRP3 Inflammasome in Kupffer Cells during Sterile Inflammatory Liver Injury
Authors: Huang Hai , Chen Hui-Wei , Evankovich John , Yan Wei , Rosborough Brian R. , Nace Gary W. , Ding Qing , Loughran Patricia , Beer-Stolz Donna , Billiar Timothy R. , Esmon Charles T. , Tsung Allan 
Published: August 2013

Abstract
Cellular processes that drive sterile inflammatory injury after hepatic ischemia/reperfusion (I/R) injury are not completely understood. Activation of the inflammasome plays a key role in response to invading intracellular pathogens, but mounting evidence suggests that it also plays a role in inflammation driven by endogenous danger-associate molecular pattern molecules released after ischemic injury. The nucleotide-binding domain, leucine-rich repeat containing protein 3 (NLRP3) inflammasome is one such process, and the mechanism by which its activation results in damage and inflammatory responses following liver I/R is unknown. In this article, we report that both NLRP3 and its downstream target caspase-1 are activated during I/R and are essential for hepatic I/R injury, because both NLRP3 and caspase-1 knockout mice are protected from injury. Furthermore, inflammasome-mediated injury is dependent on caspase-1 expression in liver nonparenchymal cells. Although upstream signals that activate the inflammasome during ischemic injury are not well characterized, we show that endogenous extracellular histones activate the NLRP3 inflammasome during liver I/R through TLR9. This occurs through TLR9-dependent generation of reactive oxygen species. This mechanism is operant in resident liver Kupffer cells, which drive innate immune responses after I/R injury by recruiting additional cell types, including neutrophils and inflammatory monocytes. These novel findings illustrate a new mechanism by which extracellular histones and activation of NLRP3 inflammasome contribute to liver damage and the activation of innate immunity during sterile inflammation.
Proinflammatory Vδ2+ T Cells Populate the Human Intestinal Mucosa and Enhance IFN-γ Production by Colonic αβ T Cells
Authors: McCarthy Neil E. , Bashir Zora , Vossenkämper Anna , Hedin Charlotte R. , Giles Edward M. , Bhattacharjee Shaumick , Brown Sabrina G. , Sanders Theodore J. , Whelan Kevin , MacDonald Thomas T. , Lindsay James O. , Stagg Andrew J. 
Published: August 2013

Abstract
In nonhuman primates, Vγ9Vδ2+ (Vδ2)T cells proliferate and accumulate in mucosal tissues following microbial activation. Human Vδ2T cells produce proinflammatory cytokines in response to bacterial species that colonize the gut, but the role played by Vδ2T cells in intestinal immunity is unknown. We hypothesized that circulating Vδ2T cells can populate the human intestine and contribute to mucosal inflammation. Cell suspensions prepared from peripheral blood and intestinal biopsies were stimulated with microbial phosphoantigen (1-hydroxy-2-methyl-2-buten-4-yl 4-diphosphate [HDMAPP]) and analyzed by flow cytometry to determine Vδ2T cell phenotype, cytokine production, and proliferative potential. Circulating Vδ2T cells expressed gut-homing integrin α4β7 (&gt;70%), which was coexpressed with skin-associated cutaneous leukocyte Ag by up to 15% of the total population. However, Vδ2T cell activation with HDMAPP and exposure to retinoic acid (signaling via retinoic acid receptor α) increased α4β7 expression and enhanced binding to mucosal addressin cell adhesion molecule-1 in vitro while simultaneously suppressing cutaneous leukocyte Ag, thereby generating a committed gut-tropic phenotype. Confocal microscopy and flow cytometry identified frequent Vδ2T cells that migrated out of human intestinal biopsies and comprised both CD103+ and CD103− subsets that produced TNF-α and IFN-γ upon phosphoantigen exposure, with more frequent cytokine-producing cells in the CD103− population. Activated intestinal Vδ2T cells expressed CD70 and HLA-DR but were unable to drive the proliferation of allogeneic naive CD4+ T cells. Instead, phosphoantigen-activated CD103− Vδ2T cells increased T-bet expression and enhanced IFN-γ production by autologous colonic αβ T cells via an IFN-γ–dependent mechanism. These data demonstrate that circulating Vδ2T cells display enhanced gut-homing potential upon microbial activation and populate the human intestinal mucosa, generating functionally distinct CD103+ and CD103− subsets that can promote inflammation by colonic αβ T cells.
Differential Roles of CXCL2 and CXCL3 and Their Receptors in Regulating Normal and Asthmatic Airway Smooth Muscle Cell Migration
Authors: Al-Alwan Laila A. , Chang Ying , Mogas Andrea , Halayko Andrew J. , Baglole Carolyn J. , Martin James G. , Rousseau Simon , Eidelman David H. , Hamid Qutayba 
Published: August 2013

Abstract
Structural cell migration plays a central role in the pathophysiology of several diseases, including asthma. Previously, we established that IL-17–induced (CXCL1, CXCL2, and CXCL3) production promoted airway smooth muscle cell (ASMC) migration, and consequently we sought to investigate the molecular mechanism of CXC-induced ASMC migration. Recombinant human CXCL1, CXCL2, and CXCL3 were used to assess migration of human primary ASMCs from normal and asthmatic subjects using a modified Boyden chamber. Neutralizing Abs or small interfering RNA (siRNA) knockdown and pharmacological inhibitors of PI3K, ERK1/2, and p38 MAPK pathways were used to investigate the receptors and the signaling pathways involved in CXC-induced ASMC migration, respectively. We established the ability of CXCL2 and CXCL3, but not CXCL1, to induce ASMC migration at the tested concentrations using normal ASMCs. We found CXCL2-induced ASMC migration to be dependent on p38 MAPK and CXCR2, whereas CXCL3-induced migration was dependent on p38 and ERK1/2 MAPK pathways via CXCR1 and CXCR2. While investigating the effect of CXCL2 and CXCL3 on asthmatic ASMC migration, we found that they induced greater migration of asthmatic ASMCs compared with normal ones. Interestingly, unlike normal ASMCs, CXCL2- and CXCL3-induced asthmatic ASMC migration was mainly mediated by the PI3K pathway through CXCR1. In conclusion, our results establish a new role of CXCR1 in ASMC migration and demonstrate the diverse mechanisms by which CXCL2 and CXCL3 mediate normal and asthmatic ASMC migration, suggesting that they may play a role in the pathogenesis of airway remodeling in asthma.
Spontaneous Loss of Tolerance of Autoreactive B Cells in Act1-Deficient Rheumatoid Factor Transgenic Mice
Authors: Giltiay Natalia V. , Lu Yi , Cullen Jaime L. , Jørgensen Trine N. , Shlomchik Mark J. , Li Xiaoxia 
Published: August 2013

Abstract
Self-reactive B cells in BALB/c AM14 transgenic (Tg) rheumatoid factor mice are not subject to central or peripheral tolerization. Instead, they remain at a stage of “clonal ignorance”; that is, they do not proliferate and differentiate into Ab-forming cells. However, the immunoregulatory mechanisms that prevent autoantibody production in these mice remain unclear. In this study, we show that crossing AM14 Tg mice to a mouse strain deficient in Act1, a molecule involved in the regulation of BAFF-R and CD40-signaling in B cells, results in spontaneous activation of AM14 Tg B cells and production of AM14-specific Abs. Three- to 5-mo-old AM14 Tg Act1−/− mice showed significant expansion of AM14 Tg B cells, including a 2- to 3-fold increase in the spleen and cervical lymph nodes compared with AM14 Tg Act1+/+ mice. Furthermore, in the presence of endogenous self-Ag (IgHa congenic background), AM14 Tg Act1−/− B cells were spontaneously activated and differentiated into Ab-forming cells. In contrast with previous studies using AM14 Tg MLR.Faslpr mice, we found that a significant number of AM14 Tg cells AM14 Tg Act1−/− mice displayed phenotypic characteristics of germinal center B cells. Anti-CD40L treatment significantly limited the expansion and activation of AM14 Tg Act1−/− B cells, suggesting that CD40L-mediated signals are required for the retention of these cells. Our results support the important role of Act1 in the regulation of self-reactive B cells and reveal how Act1 functions to prevent the production of autoantibodies.
TLR2 Signaling in Tubular Epithelial Cells Regulates NK Cell Recruitment in Kidney Ischemia–Reperfusion Injury
Authors: Kim Hye J. , Lee Jong S. , Kim Ahra , Koo Sumi , Cha Hee J. , Han Jae-A , Do Yoonkyung , Kim Kyung M. , Kwon Byoung S. , Mittler Robert S. , Cho Hong R. , Kwon Byungsuk 
Published: August 2013

Abstract
Damage-associated molecular patterns released from damaged kidney cells initiate postischemic inflammation, an essential step in the progression of kidney ischemia–reperfusion injury (IRI). However, the mechanism that coordinates this highly specific process in ischemic kidneys remains to be clarified. Previously, we demonstrated that CD137 from NK cells specifically stimulates CD137 ligand (CD137L) on tubular epithelial cells (TECs) such that TECs produced the high CXCR2 chemokine levels required for neutrophil chemotaxis. We report in the present study that endogenous TLR2 ligands released from ischemic TECs induce CCR5 chemokine expression, which is critical to promoting NK cell recruitment. By implanting CD137L−/− TECs into the kidney capsule of TLR2−/− mice, we further showed that TLR2-mediated NK cell recruitment is an uncoupled event that can occur independently of CD137L signaling in TECs, which is responsible for recruiting neutrophils. Therefore, our findings identify TECs as both a target for kidney damage and also as a master regulator that actively modulates stepwise signaling, leading to the initiation and amplification of acute sterile inflammation that inflicts kidney IRI. Being clinically important, the signaling pathway of innate receptors in epithelial cells may therefore be a good target to block acute sterile inflammation resulting from tissue damage, including kidney IRI.
SHP-1–Pyk2–Src Protein Complex and p38 MAPK Pathways Independently Regulate IL-10 Production in Lipopolysaccharide-Stimulated Macrophages
Authors: Okenwa Chinonso , Kumar Ashok , Rego Dorothy , Konarski Yulia , Nilchi Ladan , Wright Kathryn , Kozlowski Maya 
Published: August 2013

Abstract
The role of tyrosine phosphatase Src homology region 2 domain-containing phosphatase (SHP)-1 in LPS-activated cytokine production and inflammation was investigated by determining TNF-α and IL-10 production in splenic macrophages employing SHP-1–null (me/me) mouse model. LPS-stimulated me/me splenic macrophages secreted significantly less IL-10 with concomitantly elevated levels of TNF-α compared with wild-type (WT) macrophages irrespective of LPS dose and duration of stimulation. IL-10 significantly inhibited LPS-induced TNF-α production in both me/me and WT macrophages. The critical requirement for SHP-1 in regulating LPS-induced IL-10 and TNF-α production was confirmed by interfering with SHP-1 expression in WT macrophages and by reconstituting me/me macrophages with the SHP-1 gene. To delineate the role of SHP-1 in positive regulation of LPS-induced IL-10 production, signaling proteins representing SHP-1 targets were examined. The results reveal that tyrosine kinases Src and proline-rich tyrosine kinase 2 (Pyk2) regulate SHP-1–dependent LPS-induced IL-10 production and infer that optimal LPS-induced IL-10 production requires an assembly of a protein complex consisting of SHP-1–Pyk2–Src proteins. Moreover, LPS-induced IL-10 production also requires activation of the p38 MAPK independent of SHP-1 function. Overall, to our knowledge our results show for the first time that SHP-1 acts as a positive regulator of LPS-induced IL-10 production in splenic macrophages through two distinct and independent SHP-1–Pyk2–Src and p38 MAPK pathways.
Inhibition of TGF-β1 Signaling Promotes Central Memory T Cell Differentiation
Authors: Takai Shinji , Schlom Jeffrey , Tucker Joanne , Tsang Kwong Y. , Greiner John W. 
Published: August 2013

Abstract
This study affirmed that isolated CD8+ T cells express mRNA and produce TGF-β following cognate peptide recognition. Blockage of endogenous TGF-β with either a TGF-β–blocking Ab or a small molecule inhibitor of TGF-βRI enhances the generation of CD62Lhigh/CD44high central memory CD8+ T cells accompanied with a robust recall response. Interestingly, the augmentation within the central memory T cell pool occurs in lieu of cellular proliferation or activation, but with the expected increase in the ratio of the Eomesoderm/T-bet transcriptional factors. Yet, the signal transduction pathway(s) seems to be noncanonical, independent of SMAD or mammalian target of rapamycin signaling. Enhancement of central memory generation by TGF-β blockade is also confirmed in human PBMCs. The findings underscore the role(s) that autocrine TGF-β plays in T cell homeostasis and, in particular, the balance of effector/memory and central/memory T cells. These results may provide a rationale to targeting TGF-β signaling to enhance Ag-specific CD8+ T cell memory against a lethal infection or cancer.
Kinase AKT1 Negatively Controls Neutrophil Recruitment and Function in Mice
Authors: Liu Guangwei , Bi Yujing , Wang Ruoning , Shen Bo , Zhang Yan , Yang Hui , Wang Xiao , Liu Huanrong , Lu Yun , Han Fei 
Published: August 2013

Abstract
Neutrophils are critically involved in host defense and inflammatory injury. However, intrinsic signaling mechanisms controlling neutrophil recruitment and activities are poorly defined. In this article, we showed that protein kinase AKT1 (also known as PKBα) is the dominant isoform expressed in neutrophils and is downregulated upon bacterial infection and neutrophil activation. AKT1 deficiency resulted in severe disease progression accompanied by recruitment of neutrophils and enhanced bactericidal activity in the acute inflammatory lung injury (ALI) and the Staphylococcus aureus infection mouse models. Moreover, the depletion of neutrophils efficiently reversed the aggravated inflammatory response, but adoptive transfer of AKT1−/− neutrophils could potentiate the inflammatory immunity, indicating an intrinsic effect of the neutrophil in modulating inflammation in AKT1−/− mice. In the ALI model, the infiltration of neutrophils into the inflammatory site was associated with enhanced migration capacity, whereas inflammatory stimuli could promote neutrophil apoptosis. In accordance with these findings, neutralization of CXCR2 attenuated neutrophil infiltration and delayed the occurrence of inflammation. Finally, the enhanced bactericidal activity and inflammatory immunity of AKT-deficient neutrophils were mediated by a STAT1-dependent, but not a mammalian target of rapamycin–dependent, pathway. Thus, our findings indicated that the AKT1–STAT1 signaling axis negatively regulates neutrophil recruitment and activation in ALI and S. aureus infection in mice.
Protection against Tuberculosis with Homologous or Heterologous Protein/Vector Vaccine Approaches Is Not Dependent on CD8+ T Cells
Authors: Baldwin Susan L. , Ching Lance K. , Pine Samuel O. , Moutaftsi Magdalini , Lucas Elyse , Vallur Aarthy , Orr Mark T. , Bertholet Sylvie , Reed Steven G. , Coler Rhea N. 
Published: August 2013

Abstract
Considerable effort has been directed to develop Mycobacterium tuberculosis vaccines to boost bacille Calmette-Guérin or for those who cannot be immunized with bacille Calmette-Guérin. We hypothesized that CD4+ and CD8+ T cell responses with a heterologous prime/boost vaccine approach could induce long-lived vaccine efficacy against M. tuberculosis in C57BL/6 mice. We produced an adenovirus vector expressing ID93 (Ad5-ID93) for induction of CD8 T cells to use with our candidate tuberculosis vaccine, ID93/glucopyranosyl lipid adjuvant (GLA)-stable emulsion (SE), which induces potent Th1 CD4 T cells. Ad5-ID93 generates ID93-specific CD8+ T cell responses and induces protection against M. tuberculosis. When Ad5-ID93 is administered in a prime-boost strategy with ID93/GLA-SE, both CD4+ and CD8+ T cells are generated and provide protection against M. tuberculosis. In a MHC class I–deficient mouse model, all groups including the Ad5-ID93 group elicited an Ag-specific CD4+ T cell response and significantly fewer Ag-specific CD8+ T cells, but were still protected against M. tuberculosis, suggesting that CD4+ Th1 T cells could compensate for the loss of CD8+ T cells. Lastly, the order of the heterologous immunizations was critical. Long-lived vaccine protection was observed only when Ad5-ID93 was given as the boost following an ID93/GLA-SE prime. The homologous ID93/GLA-SE prime/boost regimen also induced long-lived protection. One of the correlates of protection between these two approaches was an increase in the total number of ID93-specific IFN-γ–producing CD4+ T cells 6 mo following the last immunization. Our findings provide insight into the development of vaccines not only for tuberculosis, but other diseases requiring T cell immunity.
NSP4 Is Stored in Azurophil Granules and Released by Activated Neutrophils as Active Endoprotease with Restricted Specificity
Authors: Perera Natascha C. , Wiesmüller Karl-Heinz , Larsen Maria Torp , Schacher Beate , Eickholz Peter , Borregaard Niels , Jenne Dieter E. 
Published: August 2013

Abstract
Whereas neutrophil elastase, cathepsin G, and proteinase 3 have been known as granule-associated serine proteases of neutrophils for decades, a fourth member, called neutrophil serine protease 4 (NSP4), was just recently described and provisionally characterized. In this study, we identified NSP4 as a novel azurophil granule protein of neutrophils by Western blot analyses of subcellular fractions as well as by RT-PCR analyses of neutrophil precursors from human bone marrow. The highest mRNA levels were observed in myeloblasts and promyelocytes, similar to myeloperoxidase, a marker of azurophil granules. To determine the extended sequence specificity of recombinant NSP4, we used an iterative fluorescence resonance energy transfer–based optimization strategy. In total, 142 different peptide substrates with arginine in P1 and variations at the P1′, P2′, P3, P4, and P2 positions were tested. This enabled us to construct an α1-proteinase inhibitor variant (Ile-Lys-Pro-Arg−/−Ser-Ile-Pro) with high specificity for NSP4. This tailor-made serpin was shown to form covalent complexes with all NSP4 of neutrophil lysates and supernatants of activated neutrophils, indicating that NSP4 is fully processed and stored as an already activated enzyme in azurophil granules. Moreover, cathepsin C was identified as the activator of NSP4 in vivo, as cathepsin C deficiency resulted in a complete absence of NSP4 in a Papillon-Lefèvre patient. Our in-depth analysis of NSP4 establishes this arginine-specific protease as a genuine member of preactivated serine proteases stored in azurophil granules of human neutrophils.
Multidrug Resistance in Bacteria: A Serious Patient Safety Challenge for India
Authors: Mathur Purva , Singh Sarman 
Published: August 2013

ABSTRACTPatient safety is an important issue affecting the delivery of health care in developed, transitional and developing countries. With the advancements in patient care, hitherto unknown issues relating to patient safety are emerging. An important problem endangering patient safety is infections acquired in the health care facilities. Health care associated infections (HCAIs) are no longer a local or regional problem. With the dissemination of multi-drug resistant bacteria across the globe, the problem of HCAIs has become even grimmer. The emergence of pan-resistant bacterial strains, compounded by lack of availability of new antimicrobials foretells a grave future for management of infections acquired in hospitals. Therefore, it is important to frame local policies and measures and take affirmative actions for prevention of HCAIs and reduce the burden of multi drug resistance.
Diagnostic Performance of Commercially Available Enzyme-Linked Immunosorbent Assay Kit in the Diagnosis of Extrapulmonary Tuberculosis
Authors: Sankar Manimuthu Mani , Balooni Veena , Singh Jitendra , Singh Sarman 
Published: August 2013

ABSTRACT
Objectives: Antibody based serodiagnosis tests for tuberculosis (TB) was used widely in developed and developing countries. Pathozyme Myco® immunoglobulin (Ig) M, IgA, and IgG were evaluated in pulmonary TB in many studies.
Materials and Methods: In this study we assessed this commercially available kit in detecting extrapulmonary TB (EPTB).
Results: A total of 354 subjects were recruited for the study, of which 217 (61.2%) were EPTB patients and 137 (38.7%) were subjects with no suggestive TB. The mean age was 29.7 ± 13.7 and 31.2 ± 15.2 years, respectively for two groups. Serum samples were tested for IgM, IgA, and IgG using Pathozyme Myco® IgM, IgA, and IgG kit. The individual specificity rates of IgM, IgA, and IgG were 70.8% (95% confidence interval (CI): 62.7-77.7), 77.3% (95% CI: 68.6-83.5), and 68.6%. (95% CI: 60.4-75.7); while their sensitivity was 29% (95% CI: 23.4-35.4), 24.4% (95% CI: 19.1-30.5), and 34.5% (95% CI: 28.5-41.1); respectively.
Conclusion: The serological tests either singly or in combination failed or performed poorly to diagnose EPTB.