bluuebunny/crossref_metadata_2025_split huggingface dataset:
Captopril Prevents Experimental Autoimmune Myocarditis
Authors: Godsel Lisa M. , Leon Juan S. , Wang Kegiang , Fornek Jamie L. , Molteni Agostino , Engman David M. 
Published: April 2014

Abstract
Captopril, an angiotensin-converting enzyme inhibitor, is widely used in the treatment of a variety of cardiomyopathies, but its effect on autoimmune myocarditis has not been addressed experimentally. We investigated the effect of captopril on myosin-induced experimental autoimmune myocarditis. A/J mice, immunized with syngeneic cardiac myosin, were given 75 mg/L of captopril in their drinking water. Captopril dramatically reduced the incidence and severity of myocarditis, which was accompanied by a reduction in heart weight to body weight ratio and heart weight. Captopril specifically interfered with cell-mediated immunity as myosin delayed-type hypersensitivity (DTH) was reduced, while anti-myosin Ab production was not affected. Captopril-treated, OVA-immunized mice also exhibited a decrease in OVA DTH. In myosin-immunized, untreated mice, injection of captopril directly into the test site also suppressed myosin DTH. Interestingly, captopril did not directly affect Ag-specific T cell responsiveness because neither in vivo nor in vitro captopril treatment affected the proliferation, IFN-γ secretion, or IL-2 secretion by Ag-stimulated cultured splenocytes. These results indicate that captopril ameliorates experimental autoimmune myocarditis and may act, at least in part, by interfering with the recruitment of cells to sites of inflammation and the local inflammatory environment.
α-Melanocyte-Stimulating Hormone Inhibits Allergic Airway Inflammation
Authors: Raap Ulrike , Brzoska Thomas , Sohl Sirius , Päth Günter , Emmel Jörg , Herz Udo , Braun Armin , Luger Thomas , Renz Harald 
Published: April 2014

Abstractα-Melanocyte-stimulating hormone (α-MSH) is a neuropeptide controlling melanogenesis in pigmentary cells. In addition, its potent immunomodulatory and immunosuppressive activity has been recently described in cutaneous inflammatory disorders. Whether α-MSH is also produced in the lung and might play a role in the pathogenesis of inflammatory lung conditions, including allergic bronchial asthma, is unknown. Production and functional role of α-MSH were investigated in a murine model of allergic airway inflammation. α-MSH production was detected in bronchoalveolar lavage fluids. Although aerosol challenges stimulate α-MSH production in nonsensitized mice, this rapid and marked stimulation was absent in allergic animals. Treatment of allergic mice with α-MSH resulted in suppression of airway inflammation. These effects were mediated via IL-10 production, because IL-10 knockout mice were resistant to α-MSH treatment. This study provides evidence for a novel function of α-MSH linking neuroimmune functions in allergic airway inflammation.
Distinct Role of ZAP-70 and Src Homology 2 Domain-Containing Leukocyte Protein of 76 kDa in the Prolonged Activation of Extracellular Signal-Regulated Protein Kinase by the Stromal Cell-Derived Factor-1α/CXCL12 Chemokine
Authors: Kremer Kimberly N. , Humphreys Troy D. , Kumar Ashok , Qian Nan-Xin , Hedin Karen E. 
Published: April 2014

AbstractStimulation of T lymphocytes with the ligand for the CXCR4 chemokine receptor stromal cell-derived factor-1α (SDF-1α/CXCL12), results in prolonged activation of the extracellular signal-regulated kinases (ERK) ERK1 and ERK2. Because SDF-1α is unique among several chemokines in its ability to stimulate prolonged ERK activation, this pathway is thought to mediate special functions of SDF-1α that are not shared with other chemokines. However, the molecular mechanisms of this response are poorly understood. In this study we show that SDF-1α stimulation of prolonged ERK activation in Jurkat T cells requires both the ZAP-70 tyrosine kinase and the Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76) scaffold protein. This pathway involves ZAP-70-dependent tyrosine phosphorylation of SLP-76 at one or more of its tyrosines, 113, 128, and 145. Because TCR activates ERK via SLP-76-mediated activation of the linker of activated T cells (LAT) scaffold protein, we examined the role of LAT in SDF-1α-mediated ERK activation. However, neither the SLP-76 proline-rich domain that links to GADS and LAT, nor LAT, itself are required for SDF-1α to stimulate SLP-76 tyrosine phosphorylation or to activate ERK. Together, our results describe the distinct mechanism by which SDF-1α stimulates prolonged ERK activation in T cells and indicate that this pathway is specific for cells expressing both ZAP-70 and SLP-76.
Vulnerability of Human Neurons to T Cell-Mediated Cytotoxicity
Authors: Giuliani Fabrizio , Goodyer Cynthia G. , Antel Jack P. , Yong V. Wee 
Published: April 2014

Abstract
Axonal and neuronal loss occurs in inflammatory diseases of the CNS such as multiple sclerosis. The cause of the loss remains unclear. We report that polyclonally activated T cells align along axons and soma of cultured human neurons leading to substantial neuronal death. This occurs in an allogeneic and syngeneic manner in the absence of added Ag, requires T cells to be activated, and is mediated through cell contact-dependent mechanisms involving FasL, LFA-1, and CD40 but not MHC class I. Activated CD4+ and CD8+ T cell subsets are equally neuronal cytotoxic. In contrast to neurons, other CNS cell types (oligodendrocytes and astrocytes) are not killed by T cells. These results demonstrate for the first time the high and selective vulnerability of human neurons to T cells, and suggest that when enough activated T cells accumulate in the CNS, neuronal cytotoxicity can result through Ag-independent non-MHC class I mechanisms.
The Uterine NK Cell Population Requires IL-15 but These Cells Are Not Required for Pregnancy nor the Resolution of a Listeria monocytogenes Infection
Authors: Barber Ellen M. , Pollard Jeffrey W. 
Published: April 2014

Abstract
During pregnancy in mice, uterine natural killer (uNK) cells abundantly accumulate on the mesometrial side of the placenta. In this study, we show that the presence of both mature and immature uNK cells requires IL-15. Bone marrow transplantation of NK cell-negative mice due to null mutations in the recombination-activating gene (Rag) 2/common cytokine receptor γ-chain (Rag2−/−γc−/−) genes indicated that uNK cells originate from the bone marrow and require IL-15 to develop. NK cells are thought to be central players in the immune response to intracellular pathogens such as Listeria monocytogenes, a bacterium that also has a predilection for replication in the placenta. However, IL-15−/−, NK cell-deficient mice were relatively protected from this infection compared with wild-type mice, and during pregnancy the absence of NK cells did not compromise the immune response at this site. The loss of uNK cells results in decidual abnormalities, including thickening of the arterial walls with luminal narrowing and a hypocellular decidua basalis. These defects were rescued by bone marrow transplantation of the Rag2−/−γc−/− mice that restored the uNK cell population. The decidual abnormalities in the IL-15−/− mice however did not result in infertility as gestation times and litter sizes were comparable to those of wild-type mice. Fetal weights were mildly compromised, consistent with the arterial pathologies. These results show that uNK cells are not required for successful pregnancy and that NK cells are not essential for an adequate immune response to L. monocytogenes in either pregnant or nonpregnant mice.
Identification of Circulating Fibrocytes as Precursors of Bronchial Myofibroblasts in Asthma
Authors: Schmidt Matthias , Sun Guo , Stacey Martin A. , Mori Luca , Mattoli Sabrina 
Published: April 2014

Abstract
The mechanisms contributing to airway wall remodeling in asthma are under investigation to identify appropriate therapeutic targets. Bronchial myofibroblasts would represent an important target because they play a crucial role in the genesis of subepithelial fibrosis, a characteristic feature of the remodeling process, but their origin is poorly understood. We hypothesized that they originate from fibrocytes, circulating cells with the unique characteristic of expressing the hemopoietic stem cell Ag CD34 and collagen I. In this study we show that allergen exposure induces the accumulation of fibrocyte-like cells in the bronchial mucosa of patients with allergic asthma. These cells are CD34-positive; express collagen I and α-smooth muscle actin, a marker of myofibroblasts; and localize to areas of collagen deposition below the epithelium. By tracking labeled circulating fibrocytes in a mouse model of allergic asthma, we provide evidence that fibrocytes are indeed recruited into the bronchial tissue following allergen exposure and differentiate into myofibroblasts. We also show that human circulating fibrocytes acquire the myofibroblast phenotype under in vitro stimulation with fibrogenic cytokines that are produced in exaggerated quantities in asthmatic airways. These results indicate that circulating fibrocytes may function as myofibroblast precursors and may contribute to the genesis of subepithelial fibrosis in asthma.
Mast Cells in Airway Hyporesponsive C3H/HeJ Mice Express a Unique Isoform of the Signaling Protein Ras Guanine Nucleotide Releasing Protein 4 That Is Unresponsive to Diacylglycerol and Phorbol Esters
Authors: Li Lixin , Yang Yi , Wong Guang W. , Stevens Richard L. 
Published: April 2014

Abstract
cDNAs were recently isolated from BALB/c mouse mast cells (MCs) that encode the new signaling protein mouse Ras guanine nucleotide releasing protein 4 (mRasGRP4). The present study evaluates the expression pattern and biological activity of mRasGRP4 in a variety of mouse strains. As assessed immunohistochemically and by RNA analysis, mRasGRP4 is not coordinately expressed with any of its family members. Normally, mRasGRP4 is an MC-restricted protein in tissues, and kinetic studies revealed that mRasGRP4 is expressed relatively early in developing MCs. The expression of mRasGRP4 in the fetus before granulated MCs become abundant supports the conclusion that RasGRP4 participates in MC-specific differentiation pathways. Functional studies conducted with recombinant material revealed that mRasGRP4 is a cation-dependent, diacylglycerol (DAG)-regulated, guanine nucleotide exchange factor. Immunoelectron microscopic studies revealed that mRasGRP4 resides in either the cytosol or inner leaflet of the plasma membrane of the MC, implying that DAG controls the intracellular movement of this signaling protein in c-kit-stimulated MCs. The mRasGRP4 gene resides on chromosome 7B1 within a site that is prominently linked to baseline airway reactivity in backcrossed C3H/HeJ and A/J mice. A truncated isoform of mRasGRP4 that lacks its DAG-regulatory domain was isolated from C3H/HeJ mouse MCs. Sequence analysis showed that this isoform is the result of defective splicing of the precursor transcript. MCs play a central role in allergic inflammation. The discovery of a novel isoform of mRasGRP4 in hyporesponsive mice suggests that airway reactivity is influenced by RasGRP4-dependent signaling events in pulmonary MCs.
A Site on Laminin α5, AQARSAASKVKVSMKF, Induces Inflammatory Cell Production of Matrix Metalloproteinase-9 and Chemotaxis
Authors: Adair-Kirk Tracy L. , Atkinson Jeffrey J. , Broekelmann Thomas J. , Doi Masayuki , Tryggvason Karl , Miner Jeffrey H. , Mecham Robert P. , Senior Robert M. 
Published: April 2014

Abstract
Several peptide sequences in laminin α1, the α-chain of laminin (Ln)-1, mediate biological responses in vitro, but Ln-1 is rare in vivo. Since Ln-5 and Ln-10, which contain the α3 and α5 chains, respectively, are the most prominent laminin heterotrimers in normal adult tissues and few functional domains in other laminin chains have been identified, we are investigating the α3 and α5 chains for biological activities. Incubation of mouse macrophages with the laminin α5 peptide AQARSAASKVKVSMKF resulted in marked increase in matrix metalloproteinase (MMP)-9 mRNA and gelatinolytic activity in the conditioned media, whereas the corresponding α3 peptide QQARDAANKVAIPMRF had no effect. AQARSAASKVKVSMKF also induced expression of MMP-14, while MMP-2, MMP-3, MMP-7, MMP-12, and MMP-13 were not induced by this peptide. Deletion analyses indicated that a minimal sequence of ASKVKVSMKF was sufficient for increasing MMP-9 expression. AQARSAASKVKVSMKF was also chemotactic for neutrophils and macrophages in vitro, and induced accumulation of neutrophils and macrophages in lung airspaces in vivo following intranasal instillation into mice. Comparable accumulation occurred in MMP-9-deficient mice, indicating that MMP-9 was not required for AQARSAASKVKVSMKF-induced inflammatory cell emigration in the lung. A scrambled version of the minimal peptide, KAKSFVMVSK, was inactive. These data indicate that laminin α5-derived peptides can induce inflammatory cell chemotaxis and metalloproteinase activity.
Identification and Isolation of Dominant Susceptibility Loci for Pristane-Induced Arthritis
Authors: Olofsson Peter , Holmberg Jens , Pettersson Ulf , Holmdahl Rikard 
Published: April 2014

Abstract
Rheumatoid arthritis is a chronic inflammatory autoimmune disorder, controlled by multiple genes as well as environmental factors. With animal models, like the pristane-induced arthritis (PIA) in rats, it is possible to reduce the environmental effects and the genetic heterogeneity to identify chromosomal regions harboring genes responsible for the arthritis development. The PIA model has proved to be useful for identifying gene regions controlling different phases of the disease based on intercrosses between the resistant E3 and the susceptible DA rat. We have now performed a high-powered backcross analysis that confirms previous intercross-based data but also identifies additional loci. Earlier identified PIA loci were reproduced with high significance; Pia1 (MHC region on chromosome 20), Pia4 (chromosome 12), and Pia7 (chromosome 4) are all major regulators of PIA severity and were also found to operate in concert. These three loci were verified in congenic strains using both disease- and arthritis-inflammatory-related subphenotypes as traits. We were also able to detect five new quantitative trait loci with dominant effects on PIA: Pia10, Pia12, Pia13, Pia14, and Pia15 on chromosomes 10, 6, 7, 8, and 18, respectively. These data highlight the usefulness of the statistical power obtained in a backcross of a complex disease like arthritis.
Direct Binding of Toll-Like Receptor 2 to Zymosan, and Zymosan-Induced NF-κB Activation and TNF-α Secretion Are Down-Regulated by Lung Collectin Surfactant Protein A
Authors: Sato Morihito , Sano Hitomi , Iwaki Daisuke , Kudo Kazumi , Konishi Masanori , Takahashi Hiroki , Takahashi Toru , Imaizumi Hitoshi , Asai Yasufumi , Kuroki Yoshio 
Published: April 2014

Abstract
The lung collectin surfactant protein A (SP-A) has been implicated in the regulation of pulmonary host defense and inflammation. Zymosan induces proinflammatory cytokines in immune cells. Toll-like receptor (TLR)2 has been shown to be involved in zymosan-induced signaling. We first investigated the interaction of TLR2 with zymosan. Zymosan cosedimented the soluble form of rTLR2 possessing the putative extracellular domain (sTLR2). sTLR2 directly bound to zymosan with an apparent binding constant of 48 nM. We next examined whether SP-A modulated zymosan-induced cellular responses. SP-A significantly attenuated zymosan-induced TNF-α secretion in RAW264.7 cells and alveolar macrophages in a concentration-dependent manner. Although zymosan failed to cosediment SP-A, SP-A significantly reduced zymosan-elicited NF-κB activation in TLR2-transfected human embryonic kidney 293 cells. Because we have shown that SP-A binds to sTLR2, we also examined whether SP-A affected the binding of sTLR2 to zymosan. SP-A significantly attenuated the direct binding of sTLR2 to zymosan in a concentration-dependent fashion. From these results, we conclude that 1) TLR2 directly binds zymosan, 2) SP-A can alter zymosan-TLR2 interaction, and 3) SP-A down-regulates TLR2-mediated signaling and TNF-α secretion stimulated by zymosan. This study supports an important role of SP-A in controlling pulmonary inflammation caused by microbial pathogens.
Bcl6 Is a Transcriptional Repressor for theIL-18Gene
Authors: Takeda Nobue , Arima Masafumi , Tsuruoka Nobuhide , Okada Seiji , Hatano Masahiko , Sakamoto Akemi , Kohno Yoichi , Tokuhisa Takeshi 
Published: April 2014

AbstractBcl6 functions as a sequence-specific transcriptional repressor, and Bcl6-deficient (Bcl6−/−) mice have been reported to display Th2-type inflammatory diseases in multiple organs. Since IL-18 is a potent stimulator of Th2 cells, we examined the expression of IL-18 mRNA in bone marrow-derived macrophages from Bcl6−/− mice after LPS stimulation. Here we show that the expression was strikingly up-regulated after stimulation. The expression was also up-regulated in RAW264 cells, a murine macrophage cell line, by transfection with the dominant negative type of Bcl6 gene. We identified a putative Bcl6-binding DNA sequence (IL-18BS) upstream of exon 1 of the murine IL-18 gene and three IL-18BSs in the promoter region of human IL-18 gene. Binding of Bcl6 in nuclear protein from resting RAW264 cells to murine IL-18BS was detected by gel retardation assay and chromatin immunoprecipitation assay. The binding activity was diminished gradually in RAW264 cells after LPS stimulation. However, the amount of Bcl6 protein in these cells was constant over the period examined, suggesting the functional modification of Bcl6 protein after stimulation. Furthermore, murine IL-18BS was required for Bcl6 to repress the expression of the luciferase reporter gene under control of the IL-18 promoter. Taken together, Bcl6 is a key regulator of IL-18 production by macrophages.
Thymic Export Function and T Cell Homeostasis in Patients with Relapsing Remitting Multiple Sclerosis
Authors: Hug Andreas , Korporal Mirjam , Schröder Isabella , Haas Jürgen , Glatz Katharina , Storch-Hagenlocher Brigitte , Wildemann Brigitte 
Published: April 2014

Abstract
Multiple sclerosis (MS) is an inflammatory and possibly autoimmune mediated demyelinating disease of the CNS. Autoimmunity within the CNS may be triggered by dysfunction of peripheral immune tolerance mechanisms via changes in the homeostatic composition of peripheral T cells. We have assessed the release of naive T lymphocytes from the thymus in patients with relapsing remitting MS (RRMS) to identify alterations in the equilibrium of the peripheral T cell compartment. Thymic T cell production was estimated by measuring TCR excision circles (TRECs) as a traceable molecular marker in recent thymic emigrants. A total of 46 treatment-naive patients with active RRMS and 49 gender- and age-matched healthy persons were included in the study. The levels of TREC-expressing CD4+ and CD8+ T lymphocytes were significantly decreased in MS patients, and TREC quantities overall matched those of 30 years older healthy individuals. The average concentrations of TRECs/106 CD4+ and CD8+ T lymphocytes derived from MS patients and healthy donors were 26 × 103/106 and 28 × 103/106 vs 217 × 103/106 and 169 × 103/106, respectively. To account for any influence of T cell proliferation on TREC levels, we assayed T lymphocytes from additional patients with MS and normal individuals for telomere length (n = 20) and telomerase activity (8 MS patients, 16 controls), respectively. There were no significant differences between CD4+ and CD8+ T cells from MS patients and controls. Altogether, our findings suggest that an impaired thymic export function and, as a consequence, altered ability to maintain T cell homeostasis and immune tolerance may play an important pathogenic role in RRMS.
Persistent Infection of Human Microvascular Endothelial Cells by Coxsackie B Viruses Induces Increased Expression of Adhesion Molecules
Authors: Zanone Maria M. , Favaro Enrica , Conaldi Pier G. , Greening James , Bottelli Antonella , Perin Paolo Cavallo , Klein Nigel J. , Peakman Mark , Camussi Giovanni 
Published: April 2014

AbstractNumerous studies indicate that enteroviruses, such as the Coxsackievirus (CV) group, are linked to autoimmune diseases. Virus tropism and tissue access are modulated by vascular endothelial cells (ECs), mainly at the level of the microvasculature. Data on the permissiveness of ECs to CV are, however, scanty and derived from studies on large vessel ECs. To examine the susceptibility of microvascular ECs to infection of group B CV (CVB), human dermal microvascular ECs (HMEC-1) were infected with three CVB strains, and the immunological phenotype of the infected cells was analyzed. All CVB persistently infected the EC cultures without producing overt cytopathic effects. Infected ECs retained endothelial characteristics. Release of infectious particles in cell supernatants persisted for up to 3 mo of culture. Infection up-regulated expression of the adhesion molecules ICAM-1 and VCAM-1, with the highest values detected during the first 30 days of infection (p &lt; 0.05 vs uninfected HMEC-1). CVB infection increased production of the proinflammatory cytokines, IL-6, IL-8, and TNF-α, which may account for the enhanced expression of adhesion molecules. Parallel infection of macrovascular HUVEC had less evident effects on induction of ICAM-1 and did not significantly increase expression of VCAM-1. Moreover, mononuclear cell adhesion to CVB-infected HMEC-1 monolayers was increased, compared with uninfected monolayers. These results provide evidence that small vessel ECs can harbor a persistent viral infection, resulting in quantitative modification of adhesion molecule expression, which may contribute to the selective recruitment of subsets of leukocytes during inflammatory immune responses. Furthermore, our data confirm that the behavior against a viral challenge of ECs in large vessels and microvessels may differ.
Investigating the Impact of Helminth Products on Immune Responsiveness Using a TCR Transgenic Adoptive Transfer System
Authors: Boitelle Agnès , Scales Hannah E. , Di Lorenzo Caterina , Devaney Eileen , Kennedy Malcolm W. , Garside Paul , Lawrence Catherine E. 
Published: April 2014

Abstract
Helminth infections and their products have a potent immunomodulatory effect on the host immune system and can impair immune responses against unrelated Ags. In vitro studies have suggested that the immunomodulation by helminth extracts may be the result of bystander response bias toward a Th2 phenotype and/or an Ag-specific T lymphocyte proliferative hyporesponsiveness. The aim of this study was to determine the role of these potential mechanisms of immunosuppression in vivo. Therefore, using a sensitive model of CFSE-labeled OVA-specific TCR transgenic T lymphocyte adoptive transfer, we analyzed the effect of Ascaris suum body fluid (ABF) on the kinetics and amplitude of a primary OVA-specific T cell response as well as the Th1/Th2 profile of the response in wild-type and IL-4 knockout (KO) mice. We find that inhibition of delayed-type hypersensitivity by ABF was associated with a Th1/Th2 shift in wild-type animals, but not in IL-4 KO mice. The use of this model has allowed us to demonstrate that although the kinetics of the OVA-specific primary response was not affected by ABF, the expansion of the OVA-specific T lymphocytes was significantly inhibited in both wild-type and IL-4 KO mice. This inhibition was associated with a reduced proliferative capacity of these cells in vivo, distinct from anergy.