bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction and Maintenance of Airway Responsiveness to Allergen Challenge Are Determined at the Age of Initial Sensitization
Authors: Gelfand Erwin W. , Joetham Anthony , Cui Zhi-Hua , Balhorn Annette , Takeda Katsuyuki , Taube Christian , Dakhama Azzeddine 
Published: April 2014

Abstract
Age is an important factor in determining the quantity and quality of immune responses when challenged with allergen. In a model of allergen-induced airway hyperresponsiveness and inflammation, where the sensitization phase and challenge phases can be dissociated in time, we examined the impact of age on these two phases. Sensitization of young mice (1–20 wk), but not older animals (30–40 wk), led to the development of airway hyperresponsiveness, airway eosinophilia, Th2 cytokine responses, and allergen-specific IgE, regardless of the age when the challenge phase was conducted. Thus, age at the time of initial sensitization was shown to be the critical factor dictating the nature of the response to later allergen challenge, as older mice remained responsive to allergen challenge if sensitized at a young age. These effects were shown to be mediated by lung T cells from sensitized young mice. Moreover, the failure of old sensitized mice to mediate these effects was shown not to be the result of active suppression of the responses. These data define the importance of age at initial allergen exposure in dictating subsequent responses in the lung when exposed to allergen and may help to define why asthma, even in adults, is most often initiated in early childhood.
Pneumolysin-Induced Lung Injury Is Independent of Leukocyte Trafficking into the Alveolar Space
Authors: Maus Ulrich A. , Srivastava Mrigank , Paton James C. , Mack Matthias , Everhart M. Brett , Blackwell Timothy S. , Christman John W. , Schlöndorff Detlef , Seeger Werner , Lohmeyer Jürgen 
Published: April 2014

Abstract
Pneumolysin (PLY) is a major virulence factor released by Streptococcus pneumoniae and has been implicated in the pathogenesis of pneumococcal pneumonia. In this study, we evaluated the contribution of newly recruited neutrophils and monocytes and resident alveolar macrophages to the pathogenesis of PLY-induced lung injury. Mice received either adhesion-blocking Abs to inhibit alveolar leukocyte trafficking or liposomal clodronate to deplete alveolar macrophages before intratracheal application of native PLY or its noncytotoxic derivative PdB. We found that treatment with PLY but not PdB resulted in increased lung vascular permeability. In addition, PLY also induced a decrease in the resident alveolar macrophage population, and the recruitment of peripheral blood neutrophils and monocytes into the alveolar space. Blockade of PLY-induced alveolar leukocyte trafficking by pretreatment of mice with anti-CD18 plus anti-CD49d Abs or depletion of circulating neutrophils did not attenuate the increase in lung permeability observed in response to intratracheal PLY. In addition, depletion of resident alveolar macrophages with clodronated liposomes did not reduce alveolar injury developing in response to PLY. PLY-induced lung injury was associated with only a small increase in bronchoalveolar lavage concentrations of cytokines. These data indicate that PLY-induced lung injury results from direct pneumotoxic effects on the alveolar-capillary barrier and is independent of both resident and recruited phagocytic cells.
TNF-Induced β2 Integrin Activation Involves Src Kinases and a Redox-Regulated Activation of p38 MAPK
Authors: Bouaouina Mohamed , Blouin Eric , Halbwachs-Mecarelli Lise , Lesavre Philippe , Rieu Philippe 
Published: April 2014

Abstract
We previously demonstrated that the TNF-α-induced inside-out signaling leading to β2 integrin activation is redox regulated. To identify kinases involved in this pathway, the effects of kinase inhibitors on the expression of β2 integrin activation neoepitope (clone 24) were investigated. We show that both p38 MAPK (inhibited by SB203580) and Src kinases (inhibited by PP2) are involved in β2 integrin activation by TNF and oxidants in human neutrophils. Src kinases appeared constitutively active in resting neutrophils and not further activated by TNF or oxidants in nonadherent conditions. However, PP2 blocked both TNF-induced expression of the 24 epitope and cell adhesion promoted by the integrin activating anti-CD18 KIM185 mAb, showing that both the inside-out and the outside-in signaling involve Src kinases. p38 MAPK was activated by TNF and oxidants in nonadherent conditions i.e., with 10 mM EDTA. This activation in EDTA resulted in CD11b, CD35 and CD66 up-regulation and in an oxidative response, all blocked by SB203580 and PP2. p38 MAPK was not activated upon direct integrin activation by KIM185 mAb. Thus, p38 activation allows the study to distinguish the initial transduction pathway leading to β2 integrin activation from the signaling resulting from integrin engagement. Finally, p38 MAPK activation by TNF was blocked by diphenylene iodonium, an inhibitor of flavoprotein oxidoreductase, and by the free radical scavenger N-acetylcystein. Taken together, these results demonstrate, for the first time, that constitutively activated Src tyrosine kinases and a redox-regulated activation of p38 MAPK are involved in TNF inside-out signaling leading to β2 integrin activation.
E-Prostanoid-3 Receptors Mediate the Proinflammatory Actions of Prostaglandin E2 in Acute Cutaneous Inflammation
Authors: Goulet Jennifer L. , Pace Amy J. , Key Mikelle L. , Byrum Robert S. , Nguyen MyTrang , Tilley Stephen L. , Morham Scott G. , Langenbach Robert , Stock Jeffrey L. , McNeish John D. , Smithies Oliver , Coffman Thomas M. , Koller Beverly H. 
Published: April 2014

Abstract
PGs are derived from arachidonic acid by PG-endoperoxide synthase (PTGS)-1 and PTGS2. Although enhanced levels of PGs are present during acute and chronic inflammation, a functional role for prostanoids in inflammation has not been clearly defined. Using a series of genetically engineered mice, we find that PTGS1 has the capacity to induce acute inflammation, but PTGS2 has negligible effects on the initiation of this response. Furthermore, we show that the contribution of PTGS1 is mediated by PGE2 acting through the E-prostanoid (EP)3 receptor. Moreover, in the absence of EP3 receptors, inflammation is markedly attenuated, and the addition of nonsteroidal anti-inflammatory agents does not further impair the response. These studies demonstrate that PGE2 promotes acute inflammation by activating EP3 receptors and suggest that EP3 receptors may be useful targets for anti-inflammatory therapy.
Immunoregulatory Role of Nitric Oxide in Kilham Rat Virus-Induced Autoimmune Diabetes in DR-BB Rats
Authors: Mendez Israel I. , Chung Young-Hwa , Jun Hee-Sook , Yoon Ji-Won 
Published: April 2014

Abstract
Macrophages play a critical role in the pathogenesis of Kilham rat virus (KRV)-induced autoimmune diabetes in diabetes-resistant BioBreeding (DR-BB) rats. This investigation was initiated to determine the role of macrophage-derived soluble mediators, particularly NO, in the pathogenesis of KRV-induced diabetes in DR-BB rats. We found that the expression of inducible NO synthase (iNOS), an enzyme responsible for NO production, was significantly increased during the early phase of KRV infection. Inhibition of iNOS by aminoguanidine (AG) treatment resulted in the prevention of diabetes in KRV-infected animals. The expression of IL-1β, TNF-α, and IL-12 was significantly decreased in the spleen of AG-treated, KRV-infected DR-BB rats compared with PBS-treated, KRV-infected control rats. Subsequent experiments revealed that AG treatment exerted its preventive effect in KRV-infected rats by maintaining the finely tuned immune balance normally disrupted by KRV, evidenced by a significant decrease in the expression of IFN-γ, but not IL-4, and a decrease in Th1-type chemokine receptors CCR5, CXCR3, and CXCR4. We also found that iNOS inhibition by AG decreased the KRV-induced expression of MHC class II molecules and IL-2R α-chain, resulting in the suppression of T cell activation, evidenced by the decreased cytolytic activity of CD8+ T cells. We conclude that NO plays a critical immunoregulatory role by up-regulating macrophage-derived proinflammatory cytokines, up-regulating the Th1 immune response, and activating T cells, leading to type 1 diabetes after KRV infection, whereas suppression of NO production by AG treatment prevents KRV-induced autoimmune diabetes in DR-BB rats.
Regulation of Endotoxin-Induced Proinflammatory Activation in Human Coronary Artery Cells: Expression of Functional Membrane-Bound CD14 by Human Coronary Artery Smooth Muscle Cells
Authors: Stoll Lynn L. , Denning Gerene M. , Li Wei-Gen , Rice James B. , Harrelson Allan L. , Romig Sara A. , Gunnlaugsson Skuli T. , Miller Francis J. , Weintraub Neal L. 
Published: April 2014

Abstract
Low-level endotoxemia has been identified as a powerful risk factor for atherosclerosis. However, little is known about the mechanisms that regulate endotoxin responsiveness in vascular cells. We conducted experiments to compare the relative responses of human coronary artery endothelial cells (HCAEC) and smooth muscle cells (HCASMC) to very low levels of endotoxin, and to elucidate the mechanisms that regulate endotoxin responsiveness in vascular cells. Endotoxin (≤1 ng/ml) caused production of chemotactic cytokines in HCAEC. Endotoxin-induced cytokine production was maximal at LPS-binding protein:soluble CD14 ratios &lt;1, typically observed in individuals with subclinical infection; higher LPS-binding protein:soluble CD14 ratios were inhibitory. Endotoxin potently activated HCASMC, with cytokine release &gt;10-fold higher in magnitude at &gt;10-fold lower threshold concentrations (10–30 pg/ml) compared with HCAEC. This remarkable sensitivity of HCASMC to very low endotoxin concentrations, comparable to that found in circulating monocytes, was not due to differential expression of TLR4, which was detected in HCAEC, HCASMC, and intact coronary arteries. Surprisingly, membrane-bound CD14 was detected in seven different lines of HCASMC, conferring responsiveness to endotoxin and to lipoteichoic acid, a product of Gram-positive bacteria, in these cells. These results suggest that the low levels of endotoxin associated with increased risk for atherosclerosis are sufficient to produce inflammatory responses in coronary artery cells. Because CD14 recognizes a diverse array of inflammatory mediators and functions as a pattern recognition molecule in inflammatory cells, expression of membrane-bound CD14 in HCASMC implies a potentially broader role for these cells in transducing innate immune responses in the vasculature.
Antineuroinflammatory Effect of NF-κB Essential Modifier-Binding Domain Peptides in the Adoptive Transfer Model of Experimental Allergic Encephalomyelitis
Authors: Dasgupta Subhajit , Jana Malabendu , Zhou You , Fung Yiu K. , Ghosh Sankar , Pahan Kalipada 
Published: April 2014

Abstract
It has been shown that peptides corresponding to the NF-κB essential modifier-binding domain (NBD) of IκB kinase α or IκB kinase β specifically inhibit the induction of NF-κB activation without inhibiting the basal NF-κB activity. The present study demonstrates the effectiveness of NBD peptides in inhibiting the disease process in adoptively transferred experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis. Clinical symptoms of EAE were much lower in mice receiving wild-type (wt)NBD peptides compared with those receiving mutated (m)NBD peptides. Histological and immunocytochemical analysis showed that wtNBD peptides inhibited EAE-induced spinal cord mononuclear cell invasion and normalized p65 (the RelA subunit of NF-κB) expression within the spinal cord. Analysis of lymph node cells isolated from donor and recipient mice showed that wtNBD peptides but not mNBD peptides were able to shift the immune response from a Th1 to a Th2 profile. Consistently, wtNBD peptides but not mNBD peptides inhibited the encephalitogenicity of myelin basic protein-specific T cells. Furthermore, i.p. injection of wtNBD peptides but not mNBD peptides was also able to reduce LPS- and IFN-γ-induced expression of inducible NO synthase, IL-1β, and TNF-α in vivo in the cerebellum. Taken together, our results support the conclusion that NBD peptides are antineuroinflammatory, and that NBD peptides may have therapeutic effect in neuroinflammatory disorders such as multiple sclerosis.
Regulatory Role of C5a on Macrophage Migration Inhibitory Factor Release from Neutrophils
Authors: Riedemann Niels C. , Guo Ren-Feng , Gao Hongwei , Sun Lei , Hoesel Marco , Hollmann Travis J. , Wetsel Rick A. , Zetoune Firas S. , Ward Peter A. 
Published: April 2014

Abstract
There is evidence that C5a and macrophage migration inhibitory factor (MIF) both play important roles in experimental sepsis. Humans with sepsis also show elevated levels of both mediators in the blood. Regulation of MIF during sepsis is poorly understood. We now demonstrate that neutrophil depletion greatly reduced serum MIF levels in rats and mice during the onset of sepsis after cecal ligation and puncture. In vitro, C5a induced MIF release from rat and mouse neutrophils. In vivo blockade of C5aR or absence of C5aR led to significantly reduced MIF generation during the onset of sepsis. C5a-induced release in vitro of MIF from neutrophils appeared to be due to up-regulation of MIF in cytoplasmic granules of neutrophils via activation of the protein kinase B signaling pathway together with involvement of PI3K. Our data suggest that C5a plays a role in enhancing MIF release from neutrophils in vitro and during sepsis. These findings represent a previously unrecognized function of C5a and neutrophils in the appearance of MIF in sepsis.
Blockade of Allergic Airway Inflammation Following Systemic Treatment with a B7-Dendritic Cell (PD-L2) Cross-Linking Human Antibody
Authors: Radhakrishnan Suresh , Iijima Koji , Kobayashi Takao , Rodriguez Moses , Kita Hirohito , Pease Larry R. 
Published: April 2014

Abstract
We present a novel immunotherapeutic strategy using a human B7-DC cross-linking Ab that prevents lung inflammation, airway obstruction, and hyperreactivity to allergen in a mouse model of allergic inflammatory airway disease. Dendritic cells (DC) have the ability to skew the immune response toward a Th1 or Th2 polarity. The sHIgM12 Ab functions in vitro by cross-linking the costimulatory family molecule B7-DC (PD-L2) on DC up-regulating IL-12 production, homing to lymph nodes, and T cell-activating potential of these APCs. Using chicken OVA as a model Ag, the administration of sHIgM12 Ab to BALB/c mice blocked lung inflammation, airway pathology, and responsiveness to methacholine, even after animals were presensitized and a Th2-polarized immune response was established. This therapeutic strategy was ineffective in STAT4-deficient animals, indicating that IL-12 production is critical in this system. Moreover, the polarity of the immune response upon in vitro restimulation with Ag is changed in wild-type mice, with a resulting decrease in Th2 cytokines IL-4 and IL-5 and an increase in the immunoregulatory cytokine IL-10. These studies demonstrate that the immune response of hypersensitized responders can be modulated using B7-DC cross-linking Abs, preventing allergic airway disease upon re-exposure to allergen.
An Advanced Intercross Line ResolvesEae18into Two Narrow Quantitative Trait Loci Syntenic to Multiple Sclerosis Candidate Loci
Authors: Jagodic Maja , Becanovic Kristina , Sheng Jian Rong , Wu Xingchen , Bäckdahl Liselotte , Lorentzen Johnny C. , Wallström Erik , Olsson Tomas 
Published: April 2014

AbstractIdentification of polymorphic genes regulating inflammatory diseases may unravel crucial pathogenic mechanisms. Initial steps to map such genes using linkage analysis in F2 intercross or backcross populations, however, result in broad quantitative trait loci (QTLs) containing hundreds of genes. In this study, an advanced intercross line in combination with congenic strains, was used to fine-map Eae18 on rat chromosome 10 in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE). Myelin oligodendrocyte glycoprotein-induced EAE is a chronic relapsing disease that closely mimics key features of multiple sclerosis. Congenic DA.ACI rat strains localized Eae18 to an ∼30-Mb large region. Fine-mapping was then performed in an advanced intercross line consisting of a (DA × PVG.1AV1)F7 intercross, resulting in two adjacent EAE-regulating QTLs designated Eae18a and Eae18b. The two QTLs span 5.5 and 3 Mb, respectively, and the 3-Mb Eae18b contains as few as 10 genes, including a cluster of chemokine genes (CCL1, CCL2, CCL7, and CCL11). Eae18a and Eae18b are syntenic to human chromosome 17p13 and 17q11, respectively, which both display linkage to multiple sclerosis. Thus, Eae18 consists of at least two EAE-regulating genes, providing additional evidence that clustering of disease-regulating genes in QTLs is an important phenomenon. The overlap between Eae18a and Eae18b with previously identified QTLs in humans and mice further supports the notion that susceptibility alleles in inflammatory disease are evolutionary conserved between species.
Activated Ets2 Is Required for Persistent Inflammatory Responses in the Motheaten Viable Model
Authors: Wei Guo , Guo Jianping , Doseff Andrea I. , Kusewitt Donna F. , Man Albert K. , Oshima Robert G. , Ostrowski Michael C. 
Published: April 2014

AbstractThe Ets2 transcription factor is constitutively phosphorylated on residue Thr72 in macrophages derived from mice homozygous for the motheaten viable (me-v) allele of the hemopoietic cell phosphatase (Hcph) gene. To genetically test the importance of signaling through residue Thr72 of Ets2 during inflammation, the Ets2A72 mutant allele, which cannot be phosphorylated on Thr72, was combined with the Hcphme-v allele in mice. Ets2A72/A72 moderated the inflammation-related pathology of Hcphme-v/me-v mice, as demonstrated by the increased life span and the decreased macrophage infiltration in skin and lungs of these mice. Macrophage apoptosis induced by cytokine withdrawal was also increased in the double-mutant mice. Importantly, the Ets2A72/A72 allele resulted in decreased expression of inflammatory response genes, including TNF-α, CCL3, matrix metalloprotease 9, integrin αM, and Bcl-X in alveolar macrophage. Ets2 phosphorylation was required for persistent activation of TNF-α following LPS stimulation of bone marrow-derived macrophages. The phosphorylation of Ets2 functions in the severe inflammatory phenotype of the me-v model by mediating both macrophage survival and inflammatory gene expression.
A3 Adenosine Receptor Signaling Contributes to Airway Inflammation and Mucus Production in Adenosine Deaminase-Deficient Mice
Authors: Young Hays W. J. , Molina Jose G. , Dimina Dawn , Zhong Hongyan , Jacobson Marlene , Chan Lee-Nien L. , Chan Teh-Sheng , Lee James J. , Blackburn Michael R. 
Published: April 2014

Abstract
Adenosine signaling has been implicated in chronic lung diseases such as asthma and chronic obstructive pulmonary disease; however, the specific roles of the various adenosine receptors in processes central to these disorders are not well understood. In this study, we have investigated the role(s) of the A3 adenosine receptor in adenosine-dependent pulmonary inflammation observed in adenosine deaminase (ADA)-deficient mice. The A3 receptor (A3R) was found to be expressed in eosinophils and mucus-producing cells in the airways of ADA-deficient mice. Treatment of ADA-deficient mice with MRS 1523, a selective A3R antagonist, prevented airway eosinophilia and mucus production. Similar findings were seen in the lungs of ADA/A3 double knockout mice. Although eosinophils were decreased in the airways of ADA-deficient mice following antagonism or removal of the A3R, elevations in circulating and lung interstitial eosinophils persisted, suggesting signaling through the A3R is needed for the migration of eosinophils into the airways. These findings identify an important role for the A3R in regulating lung eosinophilia and mucus production in an environment of elevated adenosine.
Mucosal T Cells Bearing TCRγδ Play a Protective Role in Intestinal Inflammation
Authors: Inagaki-Ohara Kyoko , Chinen Takatoshi , Matsuzaki Goro , Sasaki Atsuo , Sakamoto Yukiko , Hiromatsu Kenji , Nakamura-Uchiyama Fukumi , Nawa Yukifumi , Yoshimura Akihiko 
Published: April 2014

Abstract
Intestinal intraepithelial lymphocytes (IEL) bearing TCRγδ represent a major T cell population in the murine intestine. However, the role of γδ IEL in inflammatory bowel diseases (IBD) remains controversial. In this study, we show that γδ IEL is an important protective T cell population against IBD. γδ T cell-deficient (Cδ−/−) mice developed spontaneous colitis with age and showed high susceptibility to Th1-type 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis at a young age. Transfer of γδ IEL to Cδ−/− mice ameliorated TNBS-induced colitis, which correlated with decrease of IFN-γ and TNF-α production and an increase of TGF-β production by IEL. Furthermore, a high level of IL-15, which inhibits activation-induced cell death to terminate inflammation, was expressed more in intestinal epithelial cells (EC) from TNBS-treated Cδ−/− mice than in those from wild-type mice. EC from wild-type mice significantly suppressed the IFN-γ production of IEL from TNBS-treated Cδ−/− mice, whereas EC from TNBS-treated Cδ−/− mice did not. These data indicate that γδ IEL play important roles in controlling IBD by regulating mucosal T cell activation cooperated with EC function. Our study suggests that enhancement of regulatory γδ T cell activity is a possible new cell therapy for colitis.
Blockade of Late Stages of Autoimmune Diabetes by Inhibition of the Receptor for Advanced Glycation End Products
Authors: Chen Yali , Yan Shirley ShiDu , Colgan John , Zhang Hui-Ping , Luban Jeremy , Schmidt Ann Marie , Stern David , Herold Kevan C. 
Published: April 2014

Abstract
Ligation of the receptor for advanced glycation end products (RAGE) occurs during inflammation. Engagement of RAGE results in enhanced expression of addressins and it is therefore, not surprising that previous studies have shown a role of RAGE/ligand interactions in immune responses including cell/cell contact but the role of RAGE in spontaneous autoimmunity has not been clearly defined. To study the role of RAGE/ligand interactions in autoimmune diabetes, we tested the ability of soluble RAGE, a scavenger of RAGE ligands, in late stages of diabetes development in the NOD mouse-disease transferred with diabetogenic T cells and recurrent disease in NOD/scid recipients of syngeneic islet transplants. RAGE expression was detected on CD4+, CD8+, and B cells from diabetic mice and transferred to NOD/scid recipients. RAGE and its ligand, S100B, were found in the islets of NOD/scid mice that developed diabetes. Treatment of recipient NOD/scid mice with soluble RAGE prevented transfer of diabetes and delayed recurrent disease in syngeneic islet transplants. RAGE blockade was associated with increased expression of IL-10 and TGF-β in the islets from protected mice. RAGE blockade reduced the transfer of disease with enriched T cells, but had no effect when diabetes was transferred with the activated CD4+ T cell clone, BDC2.5. We conclude that RAGE/ligand interactions are involved in the differentiation of T cells to a mature pathogenic phenotype during the late stages of the development of diabetes.