bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Circuits of Resolution: Formation and Actions of Resolvins and Protectins
Authors: Bannenberg Gerard L. , Chiang Nan , Ariel Amiram , Arita Makoto , Tjonahen Eric , Gotlinger Katherine H. , Hong Song , Serhan Charles N. 
Published: April 2014

Abstract
The cellular events underlying the resolution of acute inflammation are not known in molecular terms. To identify anti-inflammatory and proresolving circuits, we investigated the temporal and differential changes in self-resolving murine exudates using mass spectrometry-based proteomics and lipidomics. Key resolution components were defined as resolution indices including Ψmax, the maximal neutrophil numbers that are present during the inflammatory response; Tmax, the time when Ψmax occurs; and the resolution interval (Ri) from Tmax to T50 when neutrophil numbers reach half Ψmax. The onset of resolution was at ∼12 h with proteomic analysis showing both haptoglobin and S100A9 levels were maximal and other exudate proteins were dynamically regulated. Eicosanoids and polyunsaturated fatty acids first appeared within 4 h. Interestingly, the docosahexaenoic acid-derived anti-inflammatory lipid mediator 10,17S-docosatriene was generated during the Ri. Administration of aspirin-triggered lipoxin A4 analog, resolvin E1, or 10,17S-docosatriene each either activated and/or accelerated resolution. For example, aspirin-triggered lipoxin A4 analog reduced Ψmax, resolvin E1 decreased both Ψmax and Tmax, whereas 10,17S-docosatriene reduced Ψmax, Tmax, and shortened Ri. Also, aspirin-triggered lipoxin A4 analog markedly inhibited proinflammatory cytokines and chemokines at 4 h (20–50% inhibition), whereas resolvin E1 and 10,17S-docosatriene’s inhibitory actions were maximal at 12 h (30–80% inhibition). Moreover, aspirin-triggered lipoxin A4 analog evoked release of the antiphlogistic cytokine TGF-β. These results characterize the first molecular resolution circuits and their major components activated by specific novel lipid mediators (i.e., resolvin E1 and 10,17S-docosatriene) to promote resolution.
Respiratory Syncytial Virus (RSV) Infection Induces Cyclooxygenase 2: A Potential Target for RSV Therapy
Authors: Richardson Joann Y. , Ottolini Martin G. , Pletneva Lioubov , Boukhvalova Marina , Zhang Shuling , Vogel Stefanie N. , Prince Gregory A. , Blanco Jorge C. G. 
Published: April 2014

Abstract
Cyclooxygenases (COXs) are rate-limiting enzymes that initiate the conversion of arachidonic acid to prostanoids. COX-2 is the inducible isoform that is up-regulated by proinflammatory agents, initiating many prostanoid-mediated pathological aspects of inflammation. The roles of cyclooxygenases and their products, PGs, have not been evaluated during respiratory syncytial virus (RSV) infection. In this study we demonstrate that COX-2 is induced by RSV infection of human lung alveolar epithelial cells with the concomitant production of PGs. COX-2 induction was dependent on the dose of virus and the time postinfection. PG production was inhibited preferentially by NS-398, a COX-2-specific inhibitor, and indomethacin, a pan-COX inhibitor, but not by SC-560, a COX-1-specific inhibitor. In vivo, COX-2 mRNA expression and protein production were strongly induced in the lungs and cells derived from bronchioalveolar lavage of cotton rats infected with RSV. The pattern of COX-2 expression in vivo in lungs is cyclical, with a final peak on day 5 that correlates with maximal histopathology. Treatment of cotton rats with indomethacin significantly mitigated lung histopathology produced by RSV. The studies described in this study provide the first evidence that COX-2 is a potential therapeutic target in RSV-induced disease.
Prenatal Blockage of Lymphotoxin β Receptor and TNF Receptor p55 Signaling Cascade Resulted in the Acceleration of Tissue Genesis for Isolated Lymphoid Follicles in the Large Intestine
Authors: Kweon Mi-Na , Yamamoto Masafumi , Rennert Paul D. , Park Eun Jeong , Lee Ah-Young , Chang Sun-Young , Hiroi Takachika , Nanno Masanobu , Kiyono Hiroshi 
Published: April 2014

Abstract
Signaling by lymphotoxin (LT) and TNF is essential for the organogenesis of secondary lymphoid tissues in systemic and mucosal compartments. In this study, we demonstrated that the progeny of mice treated with fusion protein of LTβR and IgGFc (LTβR-Ig) or LTβR-Ig plus TNFR55-Ig (double Ig) showed significantly increased numbers of isolated lymphoid follicles (ILF) in the large intestine. Interestingly, double Ig treatment accelerated the maturation of large intestinal ILF. Three-week-old progeny of double Ig-treated mice showed increased numbers of ILF in the large intestine, but not in the small intestine. Furthermore, alteration of intestinal microflora by feeding of antibiotic water did not affect the increased numbers of ILF in the large intestine of double Ig-treated mice. Most interestingly, mice that developed numerous ILF also had increased levels of activation-induced cytidine deaminase expression and numbers of IgA-expressing cells in the lamina propria of the large intestine. Taken together, these results suggest that ILF formation in the large intestine is accelerated by blockage of LTβR and TNFR55 signals in utero, and ILF, like colonic patches, might play a role in the induction of IgA response in the large intestine.
The Peritoneal Cavity Provides a Protective Niche for B1 and Conventional B Lymphocytes during Anti-CD20 Immunotherapy in Mice
Authors: Hamaguchi Yasuhito , Uchida Junji , Cain Derek W. , Venturi Guglielmo M. , Poe Jonathan C. , Haas Karen M. , Tedder Thomas F. 
Published: April 2014

Abstract
Although anti-CD20 immunotherapy effectively treats human lymphoma and autoimmune disease, the in vivo effect of immunotherapy on tissue B cells and their subsets is generally unknown. To address this, anti-mouse CD20 mAbs were used in a mouse model in which the extent and kinetics of tissue B cell depletion could be assessed in vivo. CD20 mAb treatment depleted most mature B cells within 2 days, with 95–98% of B cells in the bone marrow, blood, spleen, lymph nodes, and gut-associated lymphoid tissues depleted by day 7, including marginal zone and follicular B cells. The few spleen B cells remaining after CD20 mAb treatment included pre-B, immature, transitional, and some B1 B cells that expressed CD20 at low levels. By contrast, peritoneal cavity B cells expressed normal CD20 densities and were coated with CD20 mAb, but only 30–43% of B1 cells and 43–78% of B2 cells were depleted by day 7. Spleen B cells adoptively transferred into the peritoneal cavity were similarly resistant to mAb-induced depletion, while transferred B cells that had migrated to the spleen were depleted. However, peritoneal B1 and B2 cells were effectively depleted in mAb-treated wild-type and C3-deficient mice by thioglycolate-induced monocyte migration into this otherwise privileged niche. Inflammation-elicited effector cells did not promote peritoneal cavity B cell depletion in FcR-deficient mice treated with CD20 mAb. Thus, the majority of CD20+ cells and B cell subsets within lymphoid tissues and the peritoneum could be depleted efficiently in vivo through Fc-dependent, but C-independent pathways during anti-CD20 immunotherapy.
Primary Human Lymphocytes Transduced with NY-ESO-1 Antigen-Specific TCR Genes Recognize and Kill Diverse Human Tumor Cell Lines
Authors: Zhao Yangbing , Zheng Zhili , Robbins Paul F. , Khong Hung T. , Rosenberg Steven A. , Morgan Richard A. 
Published: April 2014

Abstract
cDNAs encoding TCR α- and β-chains specific for HLA-A2-restricted cancer-testis Ag NY-ESO-1 were cloned using a 5′RACE method from RNA isolated from a CTL generated by in vitro stimulation of PBMC with modified NY-ESO-1-specific peptide (p157–165, 9V). Functionality of the cloned TCR was confirmed by RNA electroporation of primary PBL. cDNA for these α- and β-chains were used to construct a murine stem cell virus-based retroviral vector, and high titer packaging cell lines were generated. Gene transfer efficiency in primary T lymphocytes of up to 60% was obtained without selection using a method of precoating retroviral vectors onto culture plates. Both CD4+ and CD8+ T cells could be transduced at the same efficiency. High avidity Ag recognition was demonstrated by coculture of transduced lymphocytes with target cells pulsed with low levels of peptide (&lt;20 pM). TCR-transduced CD4 T cells, when cocultured with NY-ESO-1 peptide pulsed T2 cells, could produce IFN-γ, GM-CSF, IL-4, and IL-10, suggesting CD8-independent, HLA-A2-restricted TCR activation. The transduced lymphocytes could efficiently recognize and kill HLA-A2- and NY-ESO-1-positive melanoma cell lines in a 4-h 51Cr release assay. Finally, transduced T cells could efficiently recognize NY-ESO-1-positive nonmelanoma tumor cell lines. These results strongly support the idea that redirection of normal T cell specificity by TCR gene transfer can have potential applications in tumor adoptive immunotherapy.
Critical Role of the Fifth Domain of E-Cadherin for Heterophilic Adhesion with αEβ7, But Not for Homophilic Adhesion
Authors: Shiraishi Kiyono , Tsuzaka Kensei , Yoshimoto Keiko , Kumazawa Chika , Nozaki Kyoko , Abe Tohru , Tsubota Kazuo , Takeuchi Tsutomu 
Published: April 2014

AbstractThe integrin αEβ7 is expressed on intestinal intraepithelial T lymphocytes and CD8+ T lymphocytes in inflammatory lesions near epithelial cells. Adhesion between αEβ7+ T and epithelial cells is mediated by the adhesive interaction of αEβ7 and E-cadherin; this interaction plays a key role in the damage of target epithelia. To explore the structure-function relationship of the heterophilic adhesive interaction between E-cadherin and αEβ7, we performed cell aggregation assays using L cells transfected with an extracellular domain-deletion mutant of E-cadherin. In homophilic adhesion assays, L cells transfected with wild-type or a domain 5-deficient mutant formed aggregates, whereas transfectants with domain 1-, 2-, 3-, or 4-deficient mutants did not. These results indicate that not only domain 1, but domains 2, 3, and 4 are involved in homophilic adhesion. When αEβ7+ K562 cells were incubated with L cells expressing the wild type, 23% of the resulting cell aggregates consisted of αEβ7+ K562 cells. In contrast, the binding of αEβ7+ K562 cells to L cells expressing a domain 5-deficient mutant was significantly decreased, with αEβ7+ K562 cells accounting for only 4% of the cell aggregates, while homophilic adhesion was completely preserved. These results suggest that domain 5 is involved in heterophilic adhesion with αEβ7, but not in homophilic adhesion, leading to the hypothesis that the fifth domain of E-cadherin may play a critical role in the regulation of heterophilic adhesion to αEβ7 and may be a potential target for treatments altering the adhesion of αEβ7+ T cells to epithelial cells in inflammatory epithelial diseases.
Transcriptional Regulation ofCD1D1by Ets Family Transcription Factors
Authors: Geng Yanbiao , Laslo Peter , Barton Kevin , Wang Chyung-Ru 
Published: April 2014

AbstractCD1 molecules are MHC class I-like glycoproteins specialized in presenting lipid/glycolipid Ags to T cells. The distinct cell-type specific expression of CD1D1 plays an important role in the development and function of NKT cells, a unique subset of immunoregulatory T cells. However, the mechanisms regulating CD1D1 expression are largely unknown. In this study, we have characterized the upstream region of the CD1D1 gene and identified a minimal promoter region within 200 bp from the translational start site of CD1D1 that exhibits cell-type specific promoter activity. Analysis of this region revealed an Ets binding site critical for CD1D1 promoter activity. Gel shift assays and chromatin immunoprecipitation experiments showed that Elf-1 and PU.1 bind to the CD1D1 promoter. Furthermore, we found that gene disruption of Elf-1 resulted in decreased CD1D1 expression on B cells but not other cell types, whereas conditional activation of PU.1 negatively regulated CD1D1 expression in PU.1-deficient myeloid cells. These findings are the first to demonstrate that Ets proteins are involved in the transcriptional regulation of CD1D1 and that they may function uniquely in different cell types.
X Box-Like Sequences in the MHC Class II Region Maintain Regulatory Function
Authors: Gomez Jorge A. , Majumder Parimal , Nagarajan Uma M. , Boss Jeremy M. 
Published: April 2014

AbstractSequences homologous to the canonical MHC class II (MHC-II) gene X box regulatory elements were identified within the HLA-DR subregion of the human MHC and termed X box-like (XL) sequences. Several XL box sequences were found to bind the MHC class II-specific transcription factors regulatory factor X and CIITA and were transcriptionally active. The histone code associated with the XL boxes and that of the HLA-DRA X box was determined. Using CIITA-positive and -negative B cell lines, CIITA-specific histone modifications were identified and found to be consistent among the active XL boxes. Although a remarkable similarity was observed for most modifications, differences in magnitude between the HLA-DRA promoter for modifications associated with the assembly of the general transcription factors, such as histone H3 lysine 9 acetylation and H3 lysine 4 trimethylation, distinguished the very active HLA-DRA promoter from the XL box regions. In response to IFN-γ, XL box-containing histones displayed increased acetylation, coincident with CIITA expression and that observed in B cells, suggesting that the end point mechanisms of chromatin remodeling for cell type-specific MHC-II expression were similar. Lastly, an interaction between one XL box and the HLA-DRA promoter was observed in a chromatin-looping assay. Therefore, these data provide evidence that certain XL box sequences contribute to a global increase in chromatin accessibility of the HLA-DR region in B lymphocytes and in response to IFN-γ and supports the involvement of these XL sequences in the regulation of MHC-II genes.
Epistatic Suppression of Systemic Lupus Erythematosus: Fine Mapping ofSles1to Less Than 1 Mb
Authors: Subramanian Srividya , Yim Young-Sun , Liu Kui , Tus Katalin , Zhou Xin J. , Wakeland Edward K. 
Published: April 2014

AbstractSle is a susceptibility locus for systemic autoimmunity derived from the lupus-prone NZM2410 mouse. The New Zealand White-derived suppressive modifier Sles1 was identified as a specific modifier of Sle1 and prevents the development of IgG anti-chromatin autoantibodies mediated by Sle1 on the C57BL/6 (B6) background. Fine mapping of Sles1 with truncated congenic intervals localizes it to a ∼956-kb segment of mouse chromosome 17. Sles1 completely abrogates the development of activated T and B cell populations in B6.Sle1. Despite this suppression of the Sle1-mediated cell surface activation phenotypes, B6.Sle1 Sles1 splenic B cells still exhibit intrinsic ERK phosphorylation. Classic genetic complementation tests using the nonautoimmmune 129/SvJ mouse suggests that this strain possesses a Sles1 allele complementary to that of New Zealand White, as evidenced by the lack of glomerulonephritis, splenomegaly, and antinuclear autoantibody production seen in (129 × B6.Sle1 Sles1)F1s. These findings localize and characterize the suppressive properties of Sles1 and implicate 129 as a useful strain for aiding in the identification of this elusive epistatic modifier gene.
Reduced Three-Dimensional Motility in Dehydrated Airway Mucus Prevents Neutrophil Capture and Killing Bacteria on Airway Epithelial Surfaces
Authors: Matsui Hirotoshi , Verghese Margrith W. , Kesimer Mehmet , Schwab Ute E. , Randell Scott H. , Sheehan John K. , Grubb Barbara R. , Boucher Richard C. 
Published: April 2014

Abstract
Cystic fibrosis (CF) lung disease is characterized by persistent lung infection. Thickened (concentrated) mucus in the CF lung impairs airway mucus clearance, which initiates bacterial infection. However, airways have other mechanisms to prevent bacterial infection, including neutrophil-mediated killing. Therefore, we examined whether neutrophil motility and bacterial capture and killing functions are impaired in thickened mucus. Mucus of three concentrations, representative of the range of normal (1.5 and 2.5% dry weight) and CF-like thickened (6.5%) mucus, was obtained from well-differentiated human bronchial epithelial cultures and prepared for three-dimensional studies of neutrophil migration. Neutrophil chemotaxis in the direction of gravity was optimal in 1.5% mucus, whereas 2.5% mucus best supported neutrophil chemotaxis against gravity. Lateral chemokinetic movement was fastest on airway epithelial surfaces covered with 1.5% mucus. In contrast, neutrophils exhibited little motility in any direction in thickened (6.5%) mucus. In in vivo models of airway mucus plugs, neutrophil migration was inhibited by thickened mucus (CF model) but not by normal concentrations of mucus (“normal” model). Paralleling the decreased neutrophil motility in thickened mucus, bacterial capture and killing capacity were decreased in CF-like thickened mucus. Similar results with each mucus concentration were obtained with mucus from CF cultures, indicating that inhibition of neutrophil functions was mucus concentration dependent not CF source dependent. We conclude that concentrated (“thick”) mucus inhibits neutrophil migration and killing and is a key component in the failure of defense against chronic airways infection in CF.
Critical Role for the Oligoadenylate Synthetase/RNase L Pathway in Response to IFN-β during Acute Ocular Herpes Simplex Virus Type 1 Infection
Authors: Austin Bobbie Ann , James Cassandra , Silverman Robert H. , Carr Daniel J. J. 
Published: April 2014

Abstract
We previously demonstrated that IFN-β transgene treatment protects mouse trigeminal ganglia (TG) cells from acute HSV-1 infection in vitro. However, IFN-α6 transgene treatment does not provide protection against acute HSV-1 infection in vitro, even though equivalent levels of IFN are expressed with both transgene treatments. In the present study we show that IFN-β transgene treatment before acute ocular HSV-1 infection protects mice from HSV-1-mediated mortality, whereas IFN-α6 transgene treatment does not reduce mortality. Treatment with the IFN-β and IFN-α6 transgenes was associated with increased expression of oligoadenylate synthetase (OAS)1a mRNA in the eye. However, protein kinase R mRNA was not up-regulated in the eye. In TG, only IFN-β transgene treatment reduced infectious virus levels. Furthermore, in the absence of a functional OAS pathway, corneal HSV-1 Ag expression was more widespread, and the ability of IFN-β transgene treatment to reduce infectious HSV-1 in eyes and TG was lost. Along with selective up-regulation of OAS1a mRNA expression in TG from IFN-β transgene-treated mice, we found increased levels of phospho-STAT1. Likewise, p38 MAPK phosphorylation was increased in TG from IFN-β transgene-treated mice, compared with both IFN-α6 and vector-treated mice. We also observed a time-dependent increase in JNK phosphorylation in TG from IFN-β transgene-treated vs IFN-α6 and vector-treated mice. Our results demonstrate that IFN-β is a potent antiviral cytokine that exerts protection against ocular HSV-1 infection via selective up-regulation of OAS1a mRNA in TG and by altering the phosphorylation of proteins in antiviral signaling cascades.
Lentivirus Infection Causes Neuroinflammation and Neuronal Injury in Dorsal Root Ganglia: Pathogenic Effects of STAT-1 and Inducible Nitric Oxide Synthase
Authors: Zhu Yu , Jones Gareth , Tsutsui Shigeki , Opii Wycliffe , Liu Shuhong , Silva Claudia , Butterfield D. Allan , Power Christopher 
Published: April 2014

Abstract
Distal sensory polyneuropathy (DSP) is currently the most common neurological complication of HIV infection in the developed world and is characterized by sensory neuronal injury accompanied by inflammation, which is clinically manifested as disabling pain and gait instability. We previously showed that feline immunodeficiency virus (FIV) infection of cats caused DSP together with immunosuppression in cats, similar to that observed in HIV-infected humans. In this study, we investigated the pathogenic mechanisms underlying the development of FIV-induced DSP using feline dorsal root ganglia (DRG) cultures, consisting of neurons, Schwann cells, and macrophages. FIV-infected cultures exhibited viral Ags (p24 and envelope) in macrophages accompanied by neuronal injury, indicated by neurite retraction, neuronal loss and decreased soma size, compared with mock-infected (control) cultures. FIV infection up-regulated inducible NO synthase (iNOS), STAT-1, and TNF-α mRNA levels in DRG cultures. Increased STAT-1 and iNOS mRNA levels were also observed in DRGs from FIV-infected animals relative to mock-infected controls. Similarly, immunolabeling studies of DRGs from FIV-infected animals showed that macrophages were the principal sources of STAT-1 and iNOS protein production. The iNOS inhibitor aminoguanidine reduced nitrotyrosine and protein carbonyl levels, together with preventing neuronal injury in FIV-infected DRG cultures. The present studies indicate that FIV infection of DRGs directly contributes to axonal and neuronal injury through a mechanism involving macrophage immune activation, which is mediated by STAT-1 and iNOS activation.
Invariant Vα14+ NKT Cells Participate in the Early Response to EntericListeria monocytogenesInfection
Authors: Ranson Thomas , Bregenholt Søren , Lehuen Agnes , Gaillot Olivier , Leite-de-Moraes Maria C. , Herbelin André , Berche Patrick , Di Santo James P. 
Published: April 2014

AbstractInvariant Vα14+ NKT cells are a specialized CD1-reactive T cell subset implicated in innate and adaptive immunity. We assessed whether Vα14+ NKT cells participated in the immune response against enteric Listeria monocytogenes infection in vivo. Using CD1d tetramers loaded with the synthetic lipid α-galactosylceramide (CD1d/αGC), we found that splenic and hepatic Vα14+ NKT cells in C57BL/6 mice were early producers of IFN-γ (but not IL-4) after L. monocytogenes infection. Adoptive transfer of Vα14+ NKT cells derived from TCRα° Vα14-Jα18 transgenic (TCRα°Vα14Tg) mice into alymphoid Rag°γc° mice demonstrated that Vα14+ NKT cells were capable of providing early protection against enteric L. monocytogenes infection with systemic production of IFN-γ and reduction of the bacterial burden in the liver and spleen. Rechallenge experiments demonstrated that previously immunized wild-type and Jα18° mice, but not TCRα° or TCRα°Vα14Tg mice, were able to mount adaptive responses to L. monocytogenes. These data demonstrate that Vα14+ NKT cells are able to participate in the early response against enteric L. monocytogenes through amplification of IFN-γ production, but are not essential for, nor capable of, mediating memory responses required to sterilize the host.