bluuebunny/crossref_metadata_2025_split huggingface dataset:
Critical Role of Proline-Rich Tyrosine Kinase 2 in Reversion of the Adhesion-Mediated Suppression of Reactive Oxygen Species Generation by Human Neutrophils
Authors: Zhao Tieming , Bokoch Gary M. 
Published: April 2014

Abstract
Neutrophils act as the first line of innate immune defense against invading microorganisms during infection and inflammation. The tightly regulated production of reactive oxygen species (ROS) through activation of NADPH oxidase is a major weapon used by neutrophils and other phagocytic leukocytes to combat such pathogens. Cellular adhesion signals play important physiological roles in regulating the activation of NADPH oxidase and subsequent ROS formation. We previously showed that the initial suppression of the oxidase response of chemoattractant-stimulated adherent neutrophils is mediated via inhibition of Vav1-induced activation of the NADPH oxidase regulatory GTPase Rac2 by adhesion signals. In this study we show that prior exposure of neutrophils to a number of cytokines and inflammatory mediators, including TNF-α, GM-CSF, and platelet-activating factor, overcomes the adhesion-mediated suppression of ROS formation. Proline-rich tyrosine kinase 2 (pyk2) activity is enhanced under these conditions, correlating with the restoration of Vav1 and Rac2 activities. Both dominant negative pyk2 and a pyk2-selective inhibitor prevented restoration of ROS production induced by TNF-α, GM-CSF, and platelet-activating factor, and this loss of pyk2 activity resulted in decreased Vav1 tyrosine phosphorylation and subsequent Rac2 activation. Our studies identify pyk2 as a critical regulatory component and a molecular switch to overcome the suppression of leukocyte oxidant generation by cell adhesion. This activity constitutes a mechanism by which cytokines might lead to rapid elimination of invading pathogens by adherent neutrophils under normal conditions or enhance tissue damage in pathological states.
The Role of p38 MAPK in Rhinovirus-Induced Monocyte Chemoattractant Protein-1 Production by Monocytic-Lineage Cells
Authors: Hall David J. , Bates Mary Ellen , Guar Lasya , Cronan Mark , Korpi Nichole , Bertics Paul J. 
Published: April 2014

AbstractViral respiratory infections are a major cause of asthma exacerbations and can contribute to the pathogenesis of asthma. Major group human rhinovirus enters cells by binding to the cell surface molecule ICAM-1 that is present on epithelial and monocytic lineage cells. The focus of the resulting viral infection is in bronchial epithelia. However, previous studies of the cytokine dysregulation that follows rhinovirus infection have implicated monocytic lineage cells in establishing the inflammatory environment even though productive infection is not a result. We have determined that human alveolar macrophages and human peripheral blood monocytes release MCP-1 upon exposure to human rhinovirus 16 (HRV16). Indeed, we have found p38 MAPK activation in human alveolar macrophages within 15 min of exposure to HRV16, and this activation lasts up to 1 h. The targets of p38 MAPK activation include transcriptional activators of the MCP-1 promoter. The transcription factor ATF-2, a p38 MAPK substrate, is phosphorylated 45 min after HRV16 exposure. Furthermore, IκBα, the inhibitor of the transcription factor NF-κB, is degraded. Prevention of HRV16 binding was effective in blocking p38 MAPK activation, ATF-2 phosphorylation, and MCP-1 release. This is the first report of a relationship between HRV16 exposure, MCP-1 release and monocytic-lineage cells suggesting that MCP-1 plays a role in establishing the inflammatory microenvironment initiated in the human airway upon exposure to rhinovirus.
Involvement of SHIP in TLR2-Induced Neutrophil Activation and Acute Lung Injury
Authors: Strassheim Derek , Kim Jae-Yeol , Park Jong-Sung , Mitra Sanchayita , Abraham Edward 
Published: April 2014

Abstract
The SHIP converts phosphatidylinositol 3,4,5 triphosphate to phosphatidyl 3,4 biphosphate. SHIP has negative regulatory functions on PI3K-dependent signaling pathways, which occupy important roles in modulating neutrophil functions. We used neutrophils from transgenic SHIP−/− and SHIP+/+ mice that were stimulated with peptidoglycan (PGN) to examine the role of SHIP in TLR2-induced neutrophil activation. SHIP−/− neutrophils demonstrated significantly increased activation of the PI3K-dependent kinase Akt after exposure to PGN. Release of cytokines and chemokines, including TNF-α, IL-1β, IL-6, IL-10, and MIP-2, was also increased in SHIP−/− compared with SHIP+/+ neutrophils. There was no difference in the nuclear translocation of the transcriptional factor NF-κB between PGN-stimulated SHIP−/− and SHIP+/+ neutrophils. However, phosphorylation of the p65 subunit of NF-κB, an event essential for optimal transcriptional activity of NF-κB, was increased in TLR2-activated SHIP−/− neutrophils. SHIP−/− neutrophils demonstrated greater activation of ERK1/2 and p38 MAPKs than did SHIP+/+ neutrophils after exposure to PGN. The severity of acute lung injury induced by PGN was greater in SHIP−/− as compared with SHIP+/+ mice. These results demonstrate that SHIP has a negative regulatory role in TLR2-induced neutrophil activation and in the development of related in vivo neutrophil-dependent inflammatory processes, such as acute lung injury.
Monocyte Adhesion to Xenogeneic Endothelium during Laminar Flow Is Dependent on α-Gal-Mediated Monocyte Activation
Authors: Peterson Mark D. , Jin Rongyu , Hyduk Sharon , Duchesneau Pascal , Cybulsky Myron I. , Waddell Thomas K. 
Published: April 2014

Abstract
Monocytes are the predominant inflammatory cell recruited to xenografts and participate in delayed xenograft rejection. In contrast to allogeneic leukocytes that require up-regulation of endothelial adhesion molecules to adhere and emigrate into effector tissues, we demonstrate that human monocytes adhere rapidly to unstimulated xenogeneic endothelial cells. The major xenoantigen galactoseα(1,3)galactoseβ(1,4)GlcNAc-R (α-gal) is abundantly expressed on xenogeneic endothelium. We have identified a putative receptor for α-gal on human monocytes that is a member of the C-type family of lectin receptors. Monocyte arrest under physiological flow conditions is regulated by α-gal, because cleavage or blockade results in a dramatic reduction in monocyte adhesion. Recruitment of human monocytes to unactivated xenogeneic endothelial cells requires both α4 and β2 integrins on the monocyte; binding of α-gal to monocytes results in rapid activation of β2, but not α4, integrins. Thus, activation of monocyte β2 integrins by α-gal expressed on xenogeneic endothelium provides a mechanism that may explain the dramatic accumulation of monocytes in vivo.
Evidence for a Role of Phosphodiesterase 4 in Lipopolysaccharide-Stimulated Prostaglandin E2 Production and Matrix Metalloproteinase-9 Activity in Human Amniochorionic Membranes
Authors: Oger Stéphanie , Méhats Céline , Dallot Emmanuelle , Cabrol Dominique , Leroy Marie-Josèphe 
Published: April 2014

Abstract
Chorioamniotic infection is a leading cause of preterm premature rupture of fetal membranes (amnion and chorion). Bacterial infection induces an inflammatory response characterized by elevated production of proinflammatory cytokines; the latter activate the production of both PGs that stimulate uterine contractions, and matrix metalloproteinases (MMPs) that degrade the extracellular matrix of the chorioamniotic membranes. The inflammatory response is under the control of cAMP content, which is partly regulated by phosphodiesterases (PDE). In this study, we investigated the role of the PDE4 family in the inflammatory process triggered by LPS in a model of amniochorionic explants. We found that PDE4 family is the major cAMP-PDE expressed in human fetal membranes and that PDE4 activity is increased by LPS treatment. Selective inhibition of PDE4 activity affected LPS signaling, because PDE4 inhibitors (rolipram and/or cilomilast) reduced the release of the proinflammatory cytokine TNF-α and increased the release of the anti-inflammatory cytokine IL-10. PDE4 inhibition reduced cyclooxygenase-2 protein expression and PGE2 production and also modulated MMP-9, a key mediator of the membrane rupture process, by inhibiting pro-MMP-9 mRNA expression and pro-MMP-9 activity. These results demonstrate that the PDE4 family participates in the regulation of the inflammatory response associated with fetal membrane rupture during infection. The PDE4 family may be an appropriate pharmacological target for the management of infection-induced preterm delivery.
Apoptotic Pathways Are Inhibited by Leptin Receptor Activation in Neutrophils
Authors: Bruno Andreina , Conus Sébastien , Schmid Inès , Simon Hans-Uwe 
Published: April 2014

Abstract
Leptin regulates food intake as well as metabolic, endocrine, and immune functions. It exerts proliferative and antiapoptotic activities in a variety of cell types, including T cells. Leptin also stimulates macrophages and neutrophils, and its production is increased during inflammation. In this study, we demonstrate that human neutrophils express leptin surface receptors under in vitro and in vivo conditions, and that leptin delays apoptosis of mature neutrophils in vitro. The antiapoptotic effects of leptin were concentration dependent and blocked by an anti-leptin receptor mAb. The efficacy of leptin to block neutrophil apoptosis was similar to G-CSF. Using pharmacological inhibitors, we obtained evidence that leptin initiates a signaling cascade involving PI3K- and MAPK-dependent pathways in neutrophils. Moreover, leptin delayed the cleavage of Bid and Bax, the mitochondrial release of cytochrome c and second mitochondria-derived activator of caspase, as well as the activation of both caspase-8 and caspase-3 in these cells. Taken together, leptin is a survival cytokine for human neutrophils, a finding with potential pathologic relevance in inflammatory diseases.
IL-13 Regulates the Immune Response to Inhaled Antigens
Authors: Padilla Jocelyn , Daley Eleen , Chow Anthony , Robinson Kesha , Parthasarathi Kaushik , McKenzie Andrew N. J. , Tschernig Thomas , Kurup Viswanath P. , Donaldson Debra D. , Grunig Gabriele 
Published: April 2014

AbstractThe large inhibitory effect of IL-13 blockers on the asthma phenotype prompted us to ask whether IL-13 would play a role in regulating the allergic immune response in addition to its documented effects on structural pulmonary cells. Because IL-13 does not interact with murine T or B cells, but with monocytes, macrophages, and dendritic cells (DCs), we examined the role of IL-13 in the activation of pulmonary macrophages and DCs and in the priming of an immune response to a harmless, inhaled Ag. We found that a majority of cells called “alveolar or interstitial macrophages” express CD11c at high levels (CD11chigh) and are a mixture of at least two cell types as follows: 1) cells of a mixed phenotype expressing DC and macrophage markers (CD11c, CD205, and F4/80) but little MHC class II (MHC II); and 2) DC-like cells expressing CD11c, CD205, MHC II, and costimulatory molecules. Endogenous IL-13 was necessary to induce and sustain the increase in MHC II and CD40 expression by pulmonary CD11chigh cells, demonstrated by giving an IL-13 inhibitor as a measure of prevention or reversal to allergen-primed and -challenged mice. Conversely, IL-13 given by inhalation to naive mice increased the expression of MHC II and costimulatory molecules by CD11chigh cells in an IL-4Rα-dependent manner. We found that exogenous IL-13 exaggerated the immune and inflammatory responses to an inhaled, harmless Ag, whereas endogenous IL-13 was necessary for the priming of naive mice with an inhaled, harmless Ag. These data indicate that blockade of IL-13 may have therapeutic potential for controlling the immune response to inhaled Ags.
Role of Cathepsin S-Dependent Epithelial Cell Apoptosis in IFN-γ-Induced Alveolar Remodeling and Pulmonary Emphysema
Authors: Zheng Tao , Kang Min Jong , Crothers Kristina , Zhu Zhou , Liu Wei , Lee Chun Geun , Rabach Lesley A. , Chapman Harold A. , Homer Robert J. , Aldous David , DeSanctis George , Underwood Stephen , Graupe Michael , Flavell Richard A. , Schmidt John A. , Elias Jack A. 
Published: April 2014

Abstract
Th1/Tc1 inflammation and remodeling responses characterized by tissue atrophy and destruction frequently coexist in human diseases and disorders. However, the mechanisms that are used by Th1/Tc1 cytokines, like IFN-γ, to induce these responses have not been defined. To elucidate the mechanism(s) of IFN-γ-induced tissue remodeling and destruction, we characterized the pathway that lung-targeted, transgenic IFN-γ uses to induce alveolar remodeling in a murine pulmonary emphysema modeling system. In these mice, transgenic IFN-γ caused epithelial cell DNA injury and apoptosis detectable with TUNEL (Roche) and dual annexin V and propidium iodide staining. These responses were associated with death receptor and mitochondrial apoptosis pathway activation. Importantly, apoptosis inhibition with a caspase inhibitor (N-benzylcarboxy-Val-Ala-Asp-fluoromethyl-ketone) or a null mutation of caspase-3 blocked this DNA injury and apoptosis response and significantly ameliorated IFN-γ-induced emphysema. These interventions also ameliorated IFN-γ-induced inflammation and decreased pulmonary protease burden. Selective cathepsin S inhibition and a null mutation of cathepsin S also decreased IFN-γ-induced DNA injury, apoptosis, emphysema, inflammation, and protease accumulation. These studies demonstrate that cathepsin S-dependent epithelial cell apoptosis is a critical event in the pathogenesis of IFN-γ-induced alveolar remodeling and emphysema. They also link inflammation, protease/antiprotease alterations, and protease-dependent apoptosis in the pathogenesis of Th1/Tc1 cytokine-induced tissue remodeling and destructive responses.
Curcumin Inhibits Immunostimulatory Function of Dendritic Cells: MAPKs and Translocation of NF-κB as Potential Targets
Authors: Kim Gi-Young , Kim Ki-Hyung , Lee Soong-Hwan , Yoon Man-Soo , Lee Hee-Jeong , Moon Dong-Oh , Lee Chang-Min , Ahn Soon-Cheol , Park Young Chul , Park Yeong-Min 
Published: April 2014

AbstractCurcumin has been shown to exhibit anti-inflammatory, antimutagenic, and anticarcinogenic activities. However, the effect of curcumin on the maturation and immunostimulatory function of dendritic cells (DC) largely remains unknown. In this study, we examined whether curcumin can influence surface molecule expression, cytokine production, and their underlying signaling pathways in murine bone marrow-derived DC. DC were derived from murine bone marrow cells and used as immature or LPS-stimulated mature cells. The DC were tested for surface molecule expression, cytokine production, dextran uptake, the capacity to induce T cell differentiation, and their underlying signaling pathways. Curcumin significantly suppressed CD80, CD86, and MHC class II expression, but not MHC class I expression, in the DC. The DC also exhibited impaired IL-12 expression and proinflammatory cytokine production (IL-1β, IL-6, and TNF-α). The curcumin-treated DC were highly efficient at Ag capture, via mannose receptor-mediated endocytosis. Curcumin inhibited LPS-induced MAPK activation and the translocation of NF-κB p65. In addition, the curcumin-treated DC showed an impaired induction of Th1 responses and a normal cell-mediated immune response. These novel findings provide new insight into the immunopharmacological role of curcumin in impacting on the DC. These novel findings open perspectives for the understanding of the immunopharmacological role of curcumin and therapeutic adjuvants for DC-related acute and chronic diseases.
Serum Amyloid A-Luciferase Transgenic Mice: Response to Sepsis, Acute Arthritis, and Contact Hypersensitivity and the Effects of Proteasome Inhibition
Authors: Zhang Ning , Ahsan Muhammad H. , Purchio Anthony F. , West David B. 
Published: April 2014

AbstractAcute phase serum amyloid A proteins (A-SAAs) are multifunctional apolipoproteins produced in large amounts during the acute phase of an inflammation and also during the development of chronic inflammatory diseases. In this study we present a Saa1-luc transgenic mouse model in which SAA1 gene expression can be monitored by measuring luciferase activity using a noninvasive imaging system. When challenged with LPS, TNF-α, or IL-1β, in vivo imaging of Saa1-luc mice showed a 1000- to 3000-fold induction of luciferase activity in the hepatic region that peaked 4–7 h after treatment. The induction of liver luciferase expression was consistent with an increase in SAA1 mRNA in the liver and a dramatic elevation of the serum SAA1 concentration. Ex vivo analyses revealed luciferase induction in many tissues, ranging from several-fold (brain) to &gt;5000-fold (liver) after LPS or TNF-α treatment. Pretreatment of mice with the proteasome inhibitor bortezomib significantly suppressed LPS-induced SAA1 expression. These results suggested that proteasome inhibition, perhaps through the NF-κB signaling pathway, may regulate SAA1 expression. During the development of acute arthritis triggered by intra-articular administration of zymosan, SAA1 expression was induced both locally at the knee joint and systemically in the liver, and the induction was significantly suppressed by bortezomib. Induction of SAA1 expression was also demonstrated during contact hypersensitivity induced by topical application of oxazolone. These results suggest that both local and systemic induction of A-SAA occur during inflammation and may contribute to the pathogenesis of chronic inflammatory diseases associated with amyloid deposition.
Protection of Plasminogen Activator Inhibitor-1-Deficient Mice from Nasal Allergy
Authors: Sejima Takayuki , Madoiwa Seiji , Mimuro Jun , Sugo Teruko , Okada Kiyotaka , Ueshima Shigeru , Matsuo Osamu , Ishida Takashi , Ichimura Keiichi , Sakata Yoichi 
Published: April 2014

Abstract
This study was performed to clarify the relationship between fibrinolytic components and the pathology of allergy, particularly that during the development of nasal allergy and nasal tissue changes. Intranasal OVA challenge after sensitization by i.p. administration of OVA induced a higher level of excess subepithelial collagen deposition in wild-type (WT) C57BL/6J mice than in plasminogen activator inhibitor (PAI)-1-deficient (PAI-1−/−) mice. The excess PAI-1 induction in the nasal mucosa and higher level of active PAI-1 in the nasal lavage fluid of WT-OVA mice compared with those in WT-control mice suggested that the decrease of proteolytic activity inhibits the removal of subepithelial collagen. The frequency of sneezing, nasal rubbing, nasal hyperresponsiveness, production of specific IgG1 and IgE in the serum, and production of IL-4 and IL-5 in splenocyte culture supernatant increased significantly in WT-OVA mice. In PAI-1−/− mice, these reactions were absent, and specific IgG2a in serum and IFN-γ in splenocyte culture medium increased significantly. Histopathologically, there were marked goblet cell hyperplasia and eosinophil infiltration into the nasal mucosa in WT-OVA mice, but these were absent in PAI-1−/− mice. These results indicate that the immune response in WT-OVA mice can be classified as a dominant Th2 response, which would promote collagen deposition. In contrast, the Th2 response in PAI-1−/− mice was down-regulated, and the immune response shifted from Th2-dominant reaction to a Th1-dominant one. Taken together, these findings suggest that PAI-1 plays an important role not only in thrombolysis but also in immune response.
IgA Antibodies Impair Resistance againstHelicobacter pyloriInfection: Studies on Immune Evasion in IL-10-Deficient Mice
Authors: Akhiani Ali A. , Stensson Anneli , Schön Karin , Lycke Nils Y. 
Published: April 2014

AbstractWe recently reported that Helicobacter pylori-specific Abs impair the development of gastritis and down-regulate resistance against H. pylori infection. In this study, we asked whether IgA Abs specifically can have an impact on H. pylori colonization and gastric inflammation. To obtain a sensitive model for the study of inflammation we crossed IgA- and IL-10-deficient mice. We found that IL-10−/−/IgA−/− mice were significantly less colonized than IL-10−/−/IgA+/+ mice, which in turn were less colonized than wild-type (WT) mice. The IL-10−/−/IgA−/− mice exhibited a 1.2-log reduction in bacterial counts compared with that in IL-10−/−/IgA+/+ mice, suggesting that IgA Abs rather promoted than prevented infection. The reduced colonization in IL-10−/−/IgA−/− mice was associated with the most severe gastritis observed, albeit all IL-10−/− mice demonstrated more severe gastric inflammation than wild-type mice. The gastritis score and the infiltration of CD4+ T cells into the gastric mucosa were significantly higher in IL-10−/−/IgA−/− mice than in IL-10−/−/IgA+/+ mice, arguing that IgA Abs counteracted inflammation. Moreover, following oral immunization, IL-10−/−/IgA−/− mice were significantly better protected against colonization than IL-10−/−/IgA+/+ mice. However, the stronger protection was associated with more severe postimmunization gastritis and gastric infiltration of CD4+ T cells. There was also a clear increase in complement receptor-expressing cells in IL-10−/−/IgA−/− mice, though C3b-fragment deposition in the gastric mucosa was comparable between the two. Finally, specific T cell responses to recall Ag demonstrated higher levels of IFN-γ production in IL-10−/−/IgA−/− as compared with IL-10−/−/IgA+/+ mice. Thus, it appears that IgA and IL-10 help H. pylori bacteria evade host resistance against infection.
Mannose-Containing Molecular Patterns Are Strong Inducers of Cyclooxygenase-2 Expression and Prostaglandin E2 Production in Human Macrophages
Authors: Fernández Nieves , Alonso Sara , Valera Isela , Vigo Ana González , Renedo Marta , Barbolla Luz , Crespo Mariano Sánchez 
Published: April 2014

AbstractThe induction of cyclooxygenase-2 (COX-2) and the production of PGE2 in response to pathogen-associated molecular patterns decorated with mannose moieties were studied in human monocytes and monocyte-derived macrophages (MDM). Saccharomyces cerevisiae mannan was a robust agonist, suggesting the involvement of the mannose receptor (MR). MR expression increased along the macrophage differentiation route, as judged from both its surface display assessed by flow cytometry and the ability of MDM to ingest mannosylated BSA. Treatment with mannose-BSA, a weak agonist of the MR containing a lower ratio of attached sugar compared with pure polysaccharides, before the addition of mannan inhibited COX-2 expression, whereas this was not observed when agonists other than mannan and zymosan were used. HeLa cells, which were found to express MR mRNA, showed a significant induction of COX-2 expression upon mannan challenge. Conversely, mannan did not induce COX-2 expression in HEK293 cells, which express the mRNA encoding Endo180, a parent receptor pertaining to the MR family, but not the MR itself. These data indicate that mannan is a strong inducer of COX-2 expression in human MDM, most likely by acting through the MR route. Because COX-2 products can be both proinflammatory and immunomodulatory, these results disclose a signaling route triggered by mannose-decorated pathogen-associated molecular patterns, which can be involved in both the response to pathogens and the maintenance of homeostasis.