bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis
Authors: Sheibanie Amir F. , Yen Jui-Hung , Khayrullina Tanzilya , Emig Frances , Zhang Ming , Tuma Ronald , Ganea Doina 
Published: April 2014

Abstract
Although Crohn’s disease has been traditionally considered to be Th1-mediated, the newly identified Th17 cells emerged recently as crucial participants. Th1/Th17 differentiation is controlled primarily by the IL-12 family of cytokines secreted by activated dendritic cells (DCs) and macrophages. IL-23 and IL-12/IL-27 have opposite effects, supporting the Th17 and Th1 phenotypes, respectively. We found that PGE2, a major lipid mediator released in inflammatory conditions, shifts the IL-12/IL-23 balance in DCs in favor of IL-23, and propose that high levels of PGE2 exacerbate the inflammatory process in inflammatory bowel disease through the IL-23→IL-17 axis. We assessed the effects of PGE2 on IL-12, IL-27, and IL-23 and found that PGE2 promotes IL-23, inhibits IL-12 and IL-27 expression and release from stimulated DCs, and subsequently induces IL-17 production in activated T cells. The effects of PGE2 are mediated through the EP2/EP4 receptors on DCs. In vivo, we assessed the effects of PGE analogs in an experimental model for inflammatory bowel disease and found that the exacerbation of clinical symptoms and histopathology correlated with an increase in IL-23 and IL-17, a decrease in IL-12p35 expression in colon and mesenteric lymph nodes, and a substantial increase in the number of infiltrating neutrophils and of CD4+IL-17+ T cells in the colonic tissue. These studies suggest that high levels of PGE2 exacerbate the inflammatory process through the preferential expression and release of DC-derived IL-23 and the subsequent support of the autoreactive/inflammatory Th17 phenotype.
Pulmonary Stromal-Derived Factor-1 Expression and Effect on Neutrophil Recruitment during Acute Lung Injury
Authors: Petty Joseph M. , Sueblinvong Viranuj , Lenox Christopher C. , Jones Christine C. , Cosgrove Gregory P. , Cool Carlyne D. , Rai Pradeep R. , Brown Kevin K. , Weiss Daniel J. , Poynter Matthew E. , Suratt Benjamin T. 
Published: April 2014

Abstract
The severe and protracted inflammation that characterizes acute lung injury (ALI) is driven by the ongoing recruitment of neutrophils to the lung. Although much of the cytokine signaling responsible for the initial phase of ALI has been elaborated, relatively little is known about the mechanisms governing the recruitment of neutrophils from the bone marrow to the lung in the later period of this disease. Given its previously described chemoattractant effects on marrow neutrophils, we investigated whether stromal-derived factor-1 (SDF-1) (CXCL12) might participate in this later phase of recruitment. Using immunohistochemistry to examine both banked human lung specimens from patients with ALI and lungs from mice with LPS-induced pneumonitis, we found that pulmonary SDF-1 expression increases during ALI. We further determined that both lung SDF-1 protein expression and mRNA expression rise in a delayed but sustained pattern in this mouse model and that the major source of the increase in expression appears to be the lung epithelium. Lastly, we found that expression of the SDF-1 receptor CXCR4 rises in a similar temporal pattern on neutrophils in both the blood and airspace of LPS-injured mice and that Ab-mediated SDF-1 blockade significantly attenuates late but not early pulmonary neutrophilia in this model. These results implicate SDF-1 in neutrophil recruitment to the lung in the later period of acute lung injury and suggest a novel role for this cytokine in coordinating the transition from the inflammatory response to the initiation of tissue repair.
Fibronectin- and Vitronectin-Induced Microglial Activation and Matrix Metalloproteinase-9 Expression Is Mediated by Integrins α5β1 and αvβ5
Authors: Milner Richard , Crocker Stephen J. , Hung Stephanie , Wang Xiaoyun , Frausto Ricardo F. , del Zoppo Gregory J. 
Published: April 2014

Abstract
Early in the pathogenesis of multiple sclerosis, the blood-brain barrier is compromised, which leads to deposition of the plasma proteins fibronectin and vitronectin in cerebral parenchyma. In light of our previous finding that microglial activation in vitro is strongly promoted by fibronectin and vitronectin, we set out to examine the possibility that modulation of microglial activation by fibronectin or vitronectin is an important regulatory mechanism in vivo. In an experimental autoimmune encephalomyelitis mouse model of demyelination, total brain levels of fibronectin and vitronectin were strongly increased and there was a close relationship between fibronectin and vitronectin deposition, microglial activation, and microglial expression of matrix metalloproteinase-9. In murine cell culture, flow cytometry for MHC class I and gelatin zymography revealed that microglial activation and expression of pro-matrix metalloproteinase-9 were significantly increased by fibronectin and vitronectin. Function-blocking studies showed that the influence of fibronectin and vitronectin was mediated by the α5β1 and αvβ5 integrins, respectively. Taken together, this work suggests that fibronectin and vitronectin deposition during demyelinating disease is an important influence on microglial activation state. Furthermore, it provides the first evidence that the α5β1 and αvβ5 integrins are important mediators of microglial activation.
A Previously Unrecognized Protein-Protein Interaction between TWEAK and CD163: Potential Biological Implications
Authors: Bover Laura C. , Cardó-Vila Marina , Kuniyasu Akihiko , Sun Jessica , Rangel Roberto , Takeya Motohiro , Aggarwal Bharat B. , Arap Wadih , Pasqualini Renata 
Published: April 2014

Abstract
TWEAK (TNF-like weak inducer of apoptosis) is a TNF superfamily member implicated in several mechanisms. Although fibroblast growth factor inducible 14 (Fn14)/TweakR has been reported as its receptor, an as yet unrecognized surface molecule(s) might modulate TWEAK function(s). Thus, we set out to identify TWEAK-binding proteins by screening a combinatorial peptide library. Cyclic peptides containing a consensus motif (WXDDG) bound to TWEAK specifically. These peptides were similar to CD163, a scavenger receptor cysteine-rich domain family member, restricted to the monocyte/macrophage lineage and responsible for the uptake of circulating haptoglobin-hemoglobin (Hp-Hb) complexes. Sequence profile analysis suggested that TWEAK mimicked the CD163 natural ligand (Hp-Hb). Consistently, we show dose-dependent TWEAK binding to CD163 and blockade by an anti-CD163 Ab. In a competition assay, both soluble CD163 and Fn14/TweakR were able to compete off TWEAK binding to coated Fn14/TweakR or CD163, respectively. Flow-cytometry and immunofluorescence assays showed that human monocytes (Fn14/TweakR negative and CD163 positive) bind TWEAK, thus blocking the recognition of CD163 and reducing the activation mediated by a specific mAb in these cells. We demonstrate that monocytes can sequester TWEAK from supernatants, thus preventing tumor cell apoptosis; this effect was reverted by preincubation with the peptide mimicking CD163 or with a mAb anti-CD163, indicating specificity. Finally, we show that recombinant human TWEAK binding to CD163-transfected Chinese hamster ovary cells is inhibited by the presence of either unlabeled TWEAK or the Hp-Hb complex. Together, these data are consistent with the hypothesis that CD163 either acts as a TWEAK scavenger in pathological conditions or serves as an alternate receptor for TWEAK in cells lacking Fn14/TweakR.
Characterization of Reciprocal Lmb1–4 Interval MRL-Fas
lpr and C57BL/6-Fas
lpr Congenic Mice Reveals Significant Effects from Lmb3
Authors: Santiago-Raber Marie-Laure , Haraldsson M. Katarina , Theofilopoulos Argyrios N. , Kono Dwight H. 
Published: April 2014

Abstract
Susceptibility to severe lupus in MRL-Faslpr mice requires not only the lpr mutation but also other predisposing genes. Using (MRL-Faslpr × B6-Faslpr)F2 (where B6 represents C57BL/6) intercrosses that utilize the highly susceptible MRL and poorly susceptible B6 backgrounds, we previously mapped CFA-enhanced systemic lupus-like autoimmunity to four loci, named Lmb1–4, on chromosomes 4, 5, 7, and 10. In the current study, we generated and analyzed reciprocal interval congenic mice for susceptibility to CFA-enhanced autoimmunity at all four Lmb loci. Although all loci had at least a slight effect on lymphoproliferation, only Lmb3 demonstrated a major effect on lymphoproliferation and anti-chromatin Ab levels. Further characterization of Lmb3, primarily by comparing MRL-Faslpr with MRL.B6-Lmb3 Faslpr congenic mice, revealed that it also played a significant role in spontaneous lupus, modifying lymphoproliferation, IgG and autoantibody levels, kidney disease, and survival. The less susceptible B6 Lmb3 locus was associated with a marked reduction in numbers of CD4+ and double-negative (CD4−CD8−) T cells, particularly in lymph nodes, as well as reduced T cell proliferation and enhanced T cell apoptosis, both in vivo and in vitro. IFN-γ-producing CD4+ T cells were also reduced in MRL.B6-Lmb3 Faslpr mice. Further mapping using subinterval congenic mice placed Lmb3 in the telomeric portion of chromosome 7. Thus, Lmb3, primarily through its effects on CD4+ and double-negative T cells, appears to be a highly penetrant lupus-modifying locus. Identification of the underlying genetic alteration responsible for this quantitative trait locus should provide new insights into lupus-modifying genes.
Regulation of DMBT1 via NOD2 and TLR4 in Intestinal Epithelial Cells Modulates Bacterial Recognition and Invasion
Authors: Rosenstiel Philip , Sina Christian , End Caroline , Renner Marcus , Lyer Stefan , Till Andreas , Hellmig Stephan , Nikolaus Susanna , Fölsch Ulrich R. , Helmke Burkhard , Autschbach Frank , Schirmacher Peter , Kioschis Petra , Hafner Mathias , Poustka Annemarie , Mollenhauer Jan , Schreiber Stefan 
Published: April 2014

Abstract
Mucosal epithelial cell layers are constantly exposed to a complex resident microflora. Deleted in malignant brain tumors 1 (DMBT1) belongs to the group of secreted scavenger receptor cysteine-rich proteins and is considered to be involved in host defense by pathogen binding. This report describes the regulation and function of DMBT1 in intestinal epithelial cells, which form the primary immunological barrier for invading pathogens. We report that intestinal epithelial cells up-regulate DMBT1 upon proinflammatory stimuli (e.g., TNF-α, LPS). We demonstrate that DMBT1 is a target gene for the intracellular pathogen receptor NOD2 via NF-κB activation. DMBT1 is strongly up-regulated in the inflamed intestinal mucosa of Crohn’s disease patients with wild-type, but not with mutant NOD2. We show that DMBT1 inhibits cytoinvasion of Salmonella enterica and LPS- and muramyl dipeptide-induced NF-κB activation and cytokine secretion in vitro. Thus, DMBT1 may play an important role in the first line of mucosal defense conferring immune exclusion of bacterial cell wall components. Dysregulated intestinal DMBT1 expression due to mutations in the NOD2/CARD15 gene may be part of the complex pathophysiology of barrier dysfunction in Crohn’s disease.
Loss of Discrete Memory B Cell Subsets Is Associated with Impaired Immunization Responses in HIV-1 Infection and May Be a Risk Factor for Invasive Pneumococcal Disease
Authors: Hart Melanie , Steel Alan , Clark Sally A. , Moyle Graeme , Nelson Mark , Henderson Don C. , Wilson Robert , Gotch Frances , Gazzard Brian , Kelleher Peter 
Published: April 2014

AbstractInvasive pneumococcal infection is an important cause of morbidity and mortality in HIV-1-infected individuals. B cells play an important role in maintaining serologic memory after infection. IgM memory B cells are significantly reduced in HIV-1-infected patients and their frequency is similar to that observed in other patient groups (splenectomized individuals and patients with primary Ab deficiency) who are also known to have an increased risk of invasive pneumococcal infection. Antiretroviral therapy does not restore marginal zone B cell percentages. Immunization with the 23-valent polysaccharide pneumococcal vaccine shows that HIV-1-infected patients have impaired total IgM and IgG pneumococcal vaccines compared with healthy controls. Loss of switched memory B cells was associated with impaired tetanus toxoid IgG vaccine responses. Results of this study demonstrate that defects in B cell memory subsets are associated with impaired humoral immune responses in HIV-1 patients who are receiving antiretroviral therapy and may be a contributory factor to the increased risk of invasive pneumococcal infection observed in HIV-1 infection.
Priming with Cold-Adapted Influenza A Does Not Prevent Infection but Elicits Long-Lived Protection against Supralethal Challenge with Heterosubtypic Virus
Authors: Powell Timothy J. , Strutt Tara , Reome Joyce , Hollenbaugh Joseph A. , Roberts Alan D. , Woodland David L. , Swain Susan L. , Dutton Richard W. 
Published: April 2014

Abstract
We show in this study several novel features of T cell-based heterosubtypic immunity against the influenza A virus in mice. First, T cell-mediated heterosubtypic protection against lethal challenge can be generated by a very low priming dose. Second, it becomes effective within 5–6 days. Third, it provides protection against a very high dose challenge for &gt;70 days. Also novel is the finding that strong, long-lasting, heterosubtypic protection can be elicited by priming with attenuated cold-adapted strains. We demonstrate that priming does not prevent infection of the lungs following challenge, but leads to earlier clearance of the virus and 100% survival after otherwise lethal challenge. Protection is dependent on CD8 T cells, and we show that CD4 and CD8 T cells reactive to conserved epitopes of the core proteins of the challenge virus are present after priming. Our results suggest that intranasal vaccination with cold-adapted, attenuated live virus has the potential to provide effective emergency protection against emerging influenza strains for several months.
Activation of the MAPK, ERK, following Leishmania amazonensis Infection of Macrophages
Authors: Yang Ziyan , Mosser David M. , Zhang Xia 
Published: April 2014

Abstract
IL-10 is a critical cytokine in determining host susceptibility to Leishmania spp. We previously demonstrated that macrophage-derived IL-10 could contribute to disease exacerbation, but the mechanisms whereby Leishmania infections led to IL-10 induction were not fully understood. In this study, we demonstrated that infection of macrophages with Leishmania amazonensis amastigotes led to the activation of the MAPK, ERK1/2. This activation was required, but not sufficient for IL-10 induction. In addition to ERK activation, an inflammatory stimulus, such as low m.w. hyaluronic acid from the extracellular matrix, must also be present. The combination of these two signals resulted in the superinduction of IL-10. We also demonstrated that IgG on the surface of Leishmania amastigotes was required to achieve maximal IL-10 production from infected macrophages. Surface IgG engages macrophage FcγR to induce ERK activation. Macrophages lacking FcγR, or macrophages treated with an inhibitor of spleen tyrosine kinase, the tyrosine kinase that signals via FcγR, failed to activate ERK and consequently failed to produce IL-10 following infection with Leishmania amastigotes. We confirmed that ERK1/2 activation led to the phosphorylation of histone H3 at the IL-10 promoter, and this phosphorylation allowed for the binding of the transcription factor, Sp1, to the IL-10 promoter. Finally, the administration of U0126, an inhibitor of ERK activation, to infected mice resulted in decreased lesion progression with reduced numbers of parasites in them. Thus, our findings reveal an important role of MAPK, ERK signaling in the pathogenesis of Leishmania infection.
The Mechanism Underlying Defective Fcγ Receptor-Mediated Phagocytosis by HIV-1-Infected Human Monocyte-Derived Macrophages
Authors: Leeansyah Edwin , Wines Bruce D. , Crowe Suzanne M. , Jaworowski Anthony 
Published: April 2014

AbstractClearance of IgG-opsonized erythrocytes is impaired in HIV-1-infected patients, suggesting defective FcγR-mediated phagocytosis in vivo. We have previously shown defective FcγR-mediated phagocytosis in HIV-1-infected human monocyte-derived macrophages (MDM), establishing an in vitro model for defective tissue macrophages. Inhibition was associated with decreased protein expression of FcR γ-chain, which transduces immune receptor signals via ITAM motifs. FcγRI and FcγRIIIa signal via γ-chain, whereas FcγRIIa does not. In this study, we showed that HIV-1 infection inhibited FcγRI-, but not FcγRIIa-dependent Syk activation in MDM, showing that inhibition was specific for γ-chain-dependent signaling. HIV-1 infection did not impair γ-chain mRNA levels measured by real-time PCR, suggesting a posttranscriptional mechanism of γ-chain depletion. HIV-1 infection did not affect γ-chain degradation (n = 7, p = 0.94) measured in metabolic labeling/chase experiments, whereas γ-chain biosynthesis was inhibited (n = 12, p = 0.0068). Using an enhanced GFP-expressing HIV-1 strain, we showed that FcγR-mediated phagocytosis inhibition is predominantly due to a bystander effect. Experiments in which MDM were infected in the presence of the antiretroviral drug 3TC suggest that active viral replication is required for inhibition of phagocytosis in MDM. These data suggest that HIV-1 infection may affect only γ-chain-dependent FcγR functions, but that this is not restricted to HIV-1-infected cells.
CD99 Is a Key Mediator of the Transendothelial Migration of Neutrophils
Authors: Lou Olivia , Alcaide Pilar , Luscinskas Francis W. , Muller William A. 
Published: April 2014

Abstract
Transendothelial migration of leukocytes is a critical event for inflammation, but the molecular regulation of this event is only beginning to be understood. PECAM (CD31) is a major mediator of monocyte and neutrophil transmigration, and CD99 was recently defined as a second mediator of the transmigration of monocytes. Expression of CD99 on the surface of circulating polymorphonuclear cells (PMN) is low compared with expression of CD99 on monocytes or expression of PECAM on PMN. We demonstrate here that, despite low expression of CD99, Fab of Abs against CD99 blocked over 80% of human neutrophils from transmigrating across HUVEC monolayers in an in vitro model of inflammation. Blocking CD99 on either the neutrophil or endothelial cell side resulted in a quantitatively equivalent block, suggesting a homophilic interaction between CD99 on the neutrophil and CD99 on the endothelial cell. Blocking CD99 and PECAM together resulted in additive effects, suggesting the two molecules work at distinct steps. Confocal microscopy confirmed that CD99-blocked neutrophils lodged in endothelial cell junctions at locations distal to PECAM-blocked neutrophils. The CD99-blocked PMN exhibited dynamic lateral movement within endothelial cell junctions, indicating that only the diapedesis step was blocked by interference with CD99. Anti-CD99 mAb also blocked PMN transmigration in a second in vitro model that incorporated shear stress. Taken together, the evidence demonstrates that PECAM and CD99 regulate distinct, sequential steps in the transendothelial migration of neutrophils during inflammation.
Human C-Reactive Protein Protects Mice fromStreptococcus pneumoniaeInfection without Binding to Pneumococcal C-Polysaccharide
Authors: Suresh Madathilparambil V. , Singh Sanjay K. , Ferguson Donald A. , Agrawal Alok 
Published: April 2014

AbstractHuman C-reactive protein (CRP) protects mice from lethality after infection with virulent Streptococcus pneumoniae type 3. For CRP-mediated protection, the complement system is required; however, the role of complement activation by CRP in the protection is not defined. Based on the in vitro properties of CRP, it has been assumed that protection of mice begins with the binding of CRP to pneumococcal C-polysaccharide on S. pneumoniae and subsequent activation of the mouse complement system. In this study, we explored the mechanism of CRP-mediated protection by utilizing two CRP mutants, F66A and F66A/E81A. Both mutants, unlike wild-type CRP, do not bind live virulent S. pneumoniae. We found that passively administered mutant CRP protected mice from infection as effectively as the wild-type CRP did. Infected mice injected with wild-type CRP or with mutant CRP lived longer and had lower mortality than mice that did not receive CRP. Extended survival was caused by the persistence of reduced bacteremia in mice treated with any CRP. We conclude that the CRP-mediated decrease in bacteremia and the resulting protection of mice are independent of an interaction between CRP and the pathogen and therefore are independent of the ability of CRP to activate mouse complement. It has been shown previously that the Fcγ receptors also do not contribute to such CRP-mediated protection. Combined data lead to the speculation that CRP acts on the effector cells of the immune system to enhance cell-mediated cytotoxicity and suggest investigation into the possibility of using CRP-loaded APC-based strategy to treat microbial infections.
MyD88-Dependent and MyD88-Independent Pathways in Synergy, Priming, and Tolerance between TLR Agonists
Authors: Bagchi Aranya , Herrup Elizabeth A. , Warren H. Shaw , Trigilio James , Shin Hae-Sook , Valentine Catherine , Hellman Judith 
Published: April 2014

Abstract
TLRs sense components of microorganisms and are critical host mediators of inflammation during infection. Different TLR agonists can profoundly alter inflammatory effects of one another, and studies suggest that the sequence of exposure to TLR agonists may importantly impact on responses during infection. We tested the hypothesis that synergy, priming, and tolerance between TLR agonists follow a pattern that can be predicted based on differential engagement of the MyD88-dependent (D) and the MyD88-independent (I) intracellular signaling pathways. Inflammatory effects of combinations of D and I pathway agonists were quantified in vivo and in vitro. Experiments used several D-specific agonists, an I-specific agonist (poly(I:C)), and LPS, which acts through both the D and I pathways. D-specific agonists included: peptidoglycan-associated lipoprotein, Pam3Cys, flagellin, and CpG DNA, which act through TLR2 (peptidoglycan-associated lipoprotein and Pam3Cys), TLR5, and TLR9, respectively. D and I agonists were markedly synergistic in inducing cytokine production in vivo in mice. All of the D-specific agonists were synergistic with poly(I:C) in vitro in inducing TNF and IL-6 production by mouse bone marrow-derived macrophages. Pretreatment of bone marrow-derived macrophages with poly(I:C) led to a primed response to subsequent D-specific agonists and vice versa, as indicated by increased cytokine production, and increased NF-κB translocation. Pretreatment with a D-specific agonist augmented LPS-induced IFN-β production. All D-specific agonists induced tolerance to one another. Thus, under the conditions studied here, simultaneous and sequential activation of both the D and I pathways causes synergy and priming, respectively, and tolerance is induced by agonists that act through the same pathway.