bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exacerbation of Antigen-Induced Arthritis in IFN-γ-Deficient Mice As a Result of Unrestricted IL-17 Response
Authors: Irmler Ingo M. , Gajda Mieczyslaw , Bräuer Rolf 
Published: April 2014

AbstractProinflammatory Th1 responses are believed to be involved in the induction and perpetuation of rheumatoid arthritis. However, the role of IFN-γ, the major cytokine produced by Th1 cells, is still incompletely defined. In the present study, we investigated the effects of IFN-γ deficiency (IFN-γ−/−) on the course of experimental murine Ag-induced arthritis (AIA). In the acute stage of disease, IFN-γ−/− AIA mice showed significantly increased inflammatory responses compared with wild-type C57BL/6 AIA mice, i.e., exacerbated joint swelling, increased delayed-type hypersensitivity reaction, and increased histopathological scores of arthritis. Intraarticular administration of exogenous IFN-γ at induction of AIA significantly suppressed these acute aggravation effects. Stimulated cells isolated from lymph nodes and spleen of IFN-γ−/− AIA mice showed increased production of IL-2, IL-4, IL-5, IL-6, but most prominently of IL-17. These elevations were paralleled by decreased humoral immune responses, with low serum levels of total and Ag-specific IgG (IgG1, IgG2ab, IgG2b, IgG3). At immunohistology, the knee joints of IFN-γ−/− AIA mice showed massive neutrophil granulocyte infiltration. Treatment with mAbs neutralizing IL-17 diminished the acute inflammation. In vitro, Th cell expansion and production of IL-17 upon restimulation were effectively and dose dependently inhibited by IFN-γ. These results clearly demonstrate that IFN-γ has anti-inflammatory properties during the initial phase of AIA, and indicate that IFN-γ deficiency exerts disease-promoting effects, preferentially via IL-17-modulated pathways.
The Role of IκB Kinase 2, but Not Activation of NF-κB, in the Release of CXCR3 Ligands from IFN-γ-Stimulated Human Bronchial Epithelial Cells
Authors: Tudhope Susan J. , Catley Matthew C. , Fenwick Peter S. , Russell Richard E. K. , Rumsey William L. , Newton Robert , Barnes Peter J. , Donnelly Louise E. 
Published: April 2014

Abstract
The severity of chronic obstructive pulmonary disease correlates with increased numbers of cytotoxic CD8+ T lymphocytes in the lung parenchyma. CD8+ T lymphocytes release IFN-γ which stimulates airway epithelial cells to produce CXCR3 chemokines leading to further recruitment of CD8+ T lymphocytes. To evaluate the signaling pathways involved in regulation of CXCR3 ligands, the human bronchial epithelial cell line BEAS-2B was stimulated with IFN-γ and the release of the CXCR3 ligands was measured by ELISA. The release of CXCL9, CXCL10, and CXCL11 was inhibited by an IκB kinase 2 (IKK2) selective inhibitor 2-[(Aminocarbonyl)amino]-5-[4-fluorophenyl]-3-thiophenecarboxamide (TPCA-1) (EC50 values were 0.50 ± 0.03, 0.17 ± 0.06, and 0.45 ± 0.10 μM, respectively (n = 6)) and an IKK1/2 selective inhibitor 2-amino-6-(2′cyclopropylemethoxy-6′-hydroxy-phenyl)-4-piperidin-3-yl-pyridine-3-carbonitrile (EC50 values 0.74 ± 0.40, 0.27 ± 0.06, and 0.88 ± 0.29 μM, respectively (n = 6)). The glucocorticosteroid dexamethasone had no effect on CXCR3 ligand release. The release of CXCL10 was most sensitive to inhibition by IKK2 and a role for IKK2 in CXCL10 release was confirmed by overexpression of dominant-negative adenoviral constructs to IKK2 (68.2 ± 8.3% n = 5), but not of IKK1. Neither phosphorylation of IκBα, translocation of p65 to the nucleus, or activation of a NF-κB-dependent reporter (Ad-NF-κB-luc) were detected following stimulation of BEAS-2B cells with IFN-γ. These data suggest that IKK2 is also involved in the IFN-γ-stimulated release of the CXCR3 ligands through a novel mechanism that is independent NF-κB.
Biomechanical Signals Suppress TAK1 Activation to Inhibit NF-κB Transcriptional Activation in Fibrochondrocytes
Authors: Madhavan Shashi , Anghelina Mirela , Sjostrom Danen , Dossumbekova Anar , Guttridge Denis C. , Agarwal Sudha 
Published: April 2014

AbstractExercise/joint mobilization is therapeutic for inflammatory joint diseases like rheumatoid and osteoarthritis, but the mechanisms underlying its actions remain poorly understood. We report that biomechanical signals at low/physiological magnitudes are potent inhibitors of inflammation induced by diverse proinflammatory activators like IL-1β, TNF-α, and lipopolysaccharides, in fibrochondrocytes. These signals exert their anti-inflammatory effects by inhibiting phosphorylation of TAK1, a critical point where signals generated by IL-1β, TNF-α, and LPS converge to initiate NF-κB signaling cascade and proinflammatory gene induction. Additionally, biomechanical signals inhibit multiple steps in the IL-1β-induced proinflammatory cascade downstream of IκB kinase activation to regulate IκBα and IκBβ degradation and synthesis, and promote IκBα shuttling to export nuclear NF-κB and terminate its transcriptional activity. The findings demonstrate that biomechanical forces are but another important signal that uses NF-κB pathway to regulate inflammation by switching the molecular activation of discrete molecules involved in proinflammatory gene transcription.
Vasoactive Hormone Adrenomedullin and Its Binding Protein: Anti-Inflammatory Effects by Up-Regulating Peroxisome Proliferator-Activated Receptor-γ
Authors: Miksa Michael , Wu Rongqian , Cui Xiaoxuan , Dong Weifeng , Das Padmalaya , Simms H. Hank , Ravikumar Thanjavur S. , Wang Ping 
Published: April 2014

Abstract
Sepsis is a critical inflammatory condition from which numerous patients die due to multiple organ failure and septic shock. The vasoactive hormone adrenomedullin (AM) and its binding protein (AMBP-1) are beneficial in sepsis by abrogating the progression to irreversible shock and decreasing proinflammatory cytokine release. To investigate the anti-inflammatory mechanism, we studied to determine the effect of the AM/AMBP-1 complex on peroxisome proliferator-activated receptor-γ (PPAR-γ) expression and activation by using RAW264.7 cells and a rat endotoxemia model. LPS treatment significantly decreased PPAR-γ expression in vivo and in vitro and was associated with increased TNF-α production. Treatment with AM/AMBP-1 for 4 h completely restored PPAR-γ levels in both models, resulting in TNF-α suppression. In a knockdown model using small interfering RNA in RAW264.7 macrophages, AM/AMBP-1 failed to suppress TNF-α production in the absence of PPAR-γ. LPS caused the suppression of intracellular cyclic AMP (cAMP), which was prevented by simultaneous AM/AMBP-1 treatment. Although incubation with dibutyryl cAMP significantly decreased LPS-induced ΤΝF-α release, it did not alter PPAR-γ expression. Through inhibition studies using genistein and PD98059 we found that the Pyk-2 tyrosine kinase-ERK1/2 pathway is in part responsible for the AM/AMBP-1-mediated induction of PPAR-γ and the anti-inflammatory effect. We conclude that AM/AMBP-1 is protective in sepsis due to its vasoactive properties and direct anti-inflammatory effects mediated through both the cAMP-dependent pathway and Pyk-2-ERK1/2-dependent induction of PPAR-γ.
Topically Applied 1,25-Dihydroxyvitamin D3 Enhances the Suppressive Activity of CD4+CD25+ Cells in the Draining Lymph Nodes
Authors: Gorman Shelley , Kuritzky L. Alexandra , Judge Melinda A. , Dixon Katie M. , McGlade Jacqueline P. , Mason Rebecca S. , Finlay-Jones John J. , Hart Prue H. 
Published: April 2014

Abstract
The immunomodulatory effects of vitamin D have been described following chronic oral administration to mice or supplementation of cell cultures with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D. In this study, topically applied 1,25(OH)2D3, enhanced the suppressive capacity of CD4+CD25+ cells from the draining lymph nodes. The effects of topical 1,25(OH)2D3 were compared with those of UVB irradiation, which is the environmental factor required for 1,25(OH)2D3 production in skin. CD4+ cells from the skin-draining lymph nodes (SDLN) of either 1,25(OH)2D3-treated or UVB-irradiated mice had reduced capacity to proliferate to Ags presented in vitro, and could suppress Ag-specific immune responses upon adoptive transfer into naive mice. This regulation was lost upon removal of CD4+CD25+ cells. Furthermore, purified CD4+CD25+ cells from the SDLN of 1,25(OH)2D3-treated or UVB-irradiated mice compared with equal numbers of CD4+CD25+ cells from control mice had increased capacity to suppress immune responses in both in vitro and in vivo assay systems. Following the sensitization of recipient mice with OVA, the proportion of CD4+Foxp3+ cells of donor origin significantly increased in recipients of CD4+CD25+ cells from the SDLN of 1,25(OH)2D3-treated mice, indicating that these regulatory T cells can expand in vivo with antigenic stimulation. These studies suggest that 1,25(OH)2D3 may be an important mediator by which UVB-irradiation exerts some of its immunomodulatory effects.
Estradiol Attenuates Lipopolysaccharide-Induced CXC Chemokine Ligand 8 Production by Human Peripheral Blood Monocytes
Authors: Pioli Patricia A. , Jensen Amy L. , Weaver Lehn K. , Amiel Eyal , Shen Zheng , Shen Li , Wira Charles R. , Guyre Paul M. 
Published: April 2014

AbstractRegulation of the inflammatory response is imperative to the maintenance of immune homeostasis. Activated monocytes elaborate a broad variety of proinflammatory cytokines that mediate inflammation, including CXCL8. Release of this chemokine attracts neutrophils to sites of bacterial invasion and inflammation; however, high levels of CXCL8 may result in excessive neutrophil infiltration and subsequent tissue damage. In this study, we demonstrate that 17β-estradiol (E2) attenuates LPS-induced expression of CXCL8 in human peripheral blood monocytes. Treatment of monocytes with estradiol before administration of LPS reduces CXCL8 message and protein production through an estrogen receptor-dependent mechanism, and luciferase reporter assays demonstrate that this inhibition is mediated transcriptionally. Importantly, the ability of estradiol-pretreated LPS-activated monocytes to mobilize neutrophils is impaired. These results implicate a role for estradiol in the modulation of the immune response, and may lead to an enhanced understanding of gender-based differences in inflammatory control mechanisms.
Nerve Growth Factor Promotes TLR4 Signaling-Induced Maturation of Human Dendritic Cells In Vitro through Inducible p75NTR 1
Authors: Jiang Yingming , Chen Guoyou , Zhang Yi , Lu Lin , Liu Shuxun , Cao Xuetao 
Published: April 2014

AbstractNerve growth factor (NGF) has been shown to play important roles in the differentiation, function, and survival of immune cells, contributing to immune responses and pathogenesis of autoimmune diseases. Dendritic cells (DCs) are a potent initiator for immune and inflammatory responses upon recognition of pathogens via Toll-like receptors (TLR). However, expression of NGF and its receptors on human monocyte-derived DCs (MoDCs) and the role of NGF in the response of DCs to TLR ligands remain to be investigated. In the present study, we demonstrate that there were weak expressions of NGF and no expression of NGF receptors p140TrkA and p75NTR on human immature MoDCs, however, the expression of NGF and p75NTR on MoDCs could be significantly up-regulated by LPS in a dose- and time-dependent manner. NGF could markedly promote LPS-induced expression of HLA-DR, CD40, CD80, CD83, CD86, CCR7, secretion of IL-12p40 and proinflammatory cytokines IL-1, IL-6, TNF-α, and the T cell-stimulating capacity of MoDCs, indicating that NGF can promote LPS-induced DC maturation. The promoting effect of NGF on LPS-induced MoDCs maturation could be completely abolished by pretreatment of MoDCs with p75NTR antagonist, suggesting that LPS-induced p75NTR mediates the effect. Furthermore, increased activation of the p38MAPK and NF-κB pathways has been shown to be responsible for the NGF-promoted DC maturation. Therefore, NGF facilitates TLR4 signaling-induced maturation of human DCs through LPS-up-regulated p75NTR via activation of p38 MAPK and NF-κB pathways, providing another mechanism for the involvement of NGF in the immune responses and pathogenesis of autoimmune diseases.
HVEM Signaling in Monocytes Is Mediated by Intracellular Calcium Mobilization
Authors: Heo Sook-Kyoung , Yoon Min-A , Lee Sang-Chul , Ju Seong-A , Choi Jang-Hyun , Suh Pann-Ghill , Kwon Byoung S. , Kim Byung-Sam 
Published: April 2014

AbstractHerpes virus entry mediator (HVEM) is a member of the TNF receptor (TNFR) superfamily and is expressed on many immune cells, including T and B cells, NK cells, monocytes, and neutrophils. Interaction of HVEM with its ligand, LIGHT, costimulates T cells and increases the bactericidal activity of monocytes and neutrophils. The interaction recruits cytoplasmic TNFR-associated factor adaptor proteins to the intracellular domain of HVEM. This leads to NFκB activation as a result of IκBα degradation and/or JNK/AP-1 activation, and ultimately results in the expression of genes required for cell survival, cytokine production, or cell proliferation. In this study, we show that treatment of human monocytes with recombinant human LIGHT (rhLIGHT) induces rapid elevation of intracellular calcium concentration ([Ca2+]i) in a HVEM-specific manner in parallel with TNF-α production, and enhances the bactericidal activities of monocytes. Immunoprecipitation and Western blotting analyses revealed phosphorylation of phospholipase Cγ1 (PLCγ1) but not PLCγ2. rhLIGHT-induced Ca2+response was completely abolished by silencing PLCγ1, or preincubating monocytes with PLC inhibitors, antagonists of the inositol-1,4,5-triphosphate receptor, or [Ca2+]i chelators. Furthermore, these PLC/Ca2+ inhibitors also blocked rhLIGHT-mediated IκBα degradation, generation of reactive oxygen species, TNF-α production and the bactericidal activities of monocytes. Our results indicate that Ca2+is a downstream mediator of the LIGHT/HVEM interaction in monocytes.
Complement Dependent Amplification of the Innate Response to a Cognate Microbial Ligand by the Long Pentraxin PTX3
Authors: Cotena Alessia , Maina Virginia , Sironi Marina , Bottazzi Barbara , Jeannin Pascale , Vecchi Annunciata , Corvaia Nathalie , Daha Mohamed R. , Mantovani Alberto , Garlanda Cecilia 
Published: April 2014

AbstractThe long pentraxin PTX3 is a fluid-phase pattern recognition receptor, which plays a nonredundant role in resistance against selected pathogens. PTX3 has properties similar to Abs; its production is induced by pathogen recognition, it recognizes microbial moieties, activates complement, and facilitates cellular recognition by phagocytes. The mechanisms responsible for the effector function of PTX3 in vivo have not been elucidated. OmpA, a major outer membrane protein of Gram-negative Enterobacteriaceae, is a microbial moiety recognized by PTX3. In the air pouch model, KpOmpA induces an inflammatory response, which is amplified by coadministration of PTX3 in terms of leukocyte recruitment and proinflammatory cytokine production. PTX3 did not affect the inflammatory response to LPS, a microbial moiety not recognized by PTX3. As PTX3 binds to C1q and modulates the activation of the complement cascade, we assessed the involvement of complement in the amplification of the response elicited by KpOmpA and PTX3. Experiments performed using cobra venom factor, C1-esterase inhibitor, and soluble complement receptor 1 indicate that PTX3 amplifies the inflammatory response to KpOmpA through complement activation. The results reported here demonstrate that PTX3 activates a complement-dependent humoral amplification loop of the innate response to a microbial ligand.
Hsp72 Induces Inflammation and Regulates Cytokine Production in Airway Epithelium through a TLR4- and NF-κB-Dependent Mechanism
Authors: Chase Margaret A. , Wheeler Derek S. , Lierl Kristin M. , Hughes Valerie S. , Wong Hector R. , Page Kristen 
Published: April 2014

Abstract
Heat shock proteins are generally regarded as intracellular proteins acting as molecular chaperones; however, Hsp72 is also detected in the extracellular compartment. Hsp72 has been identified in the bronchoalveolar lavage fluid (BALF) of patients with acute lung injury. To address whether Hsp72 directly activated airway epithelium, human bronchial epithelial cells (16HBE14o-) were treated with recombinant Hsp72. Hsp72 induced a dose-dependent increase in IL-8 expression, which was inhibited by the NF-κB inhibitor parthenolide. Hsp72 induced activation of NF-κB, as evidenced by NF-κB trans-activation and by p65 RelA and p50 NF-κB1 binding to DNA. Endotoxin contamination of the Hsp72 preparation was not responsible for these effects. Next, BALB/c mice were challenged with a single intratracheal inhalation of Hsp72 and killed 4 h later. Hsp72 induced significant up-regulation of KC, TNF-α, neutrophil recruitment, and myeloperoxidase in the BALF. A similar challenge with Hsp72 in TLR4 mutant mice did not stimulate the inflammatory response, stressing the importance of TLR4 in Hsp72-mediated lung inflammation. Last, cultured mouse tracheal epithelial cells (MTEC) from BALB/c and TLR4 mutant and wild-type mice were treated ex vivo with Hsp72. Hsp72 induced a significant increase in KC expression from BALB/c and wild-type MTEC in an NF-κB-dependent manner; however, TLR4 mutant MTEC had minimal cytokine release. Taken together, these data suggest that Hsp72 is released and biologically active in the BALF and can regulate airway epithelial cell cytokine expression in a TLR4 and NF-κB-dependent mechanism.
Decline in the Frequencies of Borrelia burgdorferi OspA161–175-Specific T Cells after Antibiotic Therapy in HLA-DRB1*0401-Positive Patients with Antibiotic-Responsive or Antibiotic-Refractory Lyme Arthritis
Authors: Kannian Priya , Drouin Elise E. , Glickstein Lisa , Kwok William W. , Nepom Gerald T. , Steere Allen C. 
Published: April 2014

Abstract
Synovitis in patients with antibiotic-refractory Lyme arthritis persists for months to several years after antibiotic therapy. This course, which may result from infection-induced autoimmunity, is associated with T cell recognition of Borrelia burgdorferi outer surface protein A (OspA161–175) and with HLA-DR molecules that bind this epitope, including the DRB1*0401 molecule. In this study, we used tetramer reagents to determine the frequencies of OspA161–175-specific T cells in samples of PBMC and synovial fluid mononuclear cells (SFMC) from 13 DRB1*0401-positive patients with antibiotic-responsive or antibiotic-refractory arthritis. Initially, three of the six patients (50%) with antibiotic-responsive arthritis and four of the seven patients (57%) with antibiotic-refractory arthritis had frequencies of OspA161–175-specific CD4+ T cells in peripheral blood above the cutoff value of 4 per 105 cells. Among the five patients with concomitant PBMC and SFMC, four (80%) had OspA tetramer-positive cells at both sites, but the mean frequency of such cells was 16 times higher in SFMC, reaching levels as high as 1,177 per 105 cells. In the two patients in each patient group in whom serial samples were available, the frequencies of OspA161–175-specific T cells declined to low or undetectable levels during or soon after antibiotic therapy, months before the resolution of synovitis in the two patients with antibiotic-refractory arthritis. Thus, the majority of patients with Lyme arthritis initially have increased frequencies of OspA161–175-specific T cells. However, the marked decline in the frequency of such cells with antibiotic therapy suggests that persistent synovitis in the refractory group is not perpetuated by these cells.
VH4 Gene Segments Dominate the Intrathecal Humoral Immune Response in Multiple Sclerosis
Authors: Owens Gregory P. , Winges Kimberly M. , Ritchie Alanna M. , Edwards Sydni , Burgoon Mark P. , Lehnhoff Laura , Nielsen Kirsten , Corboy John , Gilden Donald H. , Bennett Jeffrey L. 
Published: April 2014

Abstract
A characteristic feature of the CNS inflammatory response in multiple sclerosis (MS) is the intrathecal synthesis of IgG and the presence of oligoclonal bands. A strong correlation between CD138+ plasma blast numbers in MS cerebrospinal fluid (CeSF) and intrathecal IgG synthesis suggests that these cells are the major Ab-secreting cell type in MS CeSF. Sequencing of V regions from CD138+ cells in MS CeSF has revealed somatically mutated and expanded IgG clonotypes consistent with an Ag-targeted response. In the present study, single-cell RT-PCR analysis of CD138+ cells from 11 MS patients representing differing clinical courses and stages of disease identified expansion of CD138+ cells with functionally rearranged VH4 gene segments as an overriding feature of MS CeSF repertoires. VH4 dominance was attributed to the preferential selection of specific VH4 genes, particularly gene segment VH4-39, which displayed a significant enrichment in CeSF compared with MS peripheral blood B cells. A modest increase in VH4 prevalence among MS peripheral blood IgG memory cells was also noted, suggesting that factors shaping the CD138 repertoire in CeSF might also influence the peripheral IgG memory cell pool. These results indicate a highly restricted B cell response in MS. Identifying the targets of CeSF plasma cells may yield insights into disease pathogenesis.
Demethylation of CD40LG on the Inactive X in T Cells from Women with Lupus
Authors: Lu Qianjin , Wu Ailing , Tesmer Laura , Ray Donna , Yousif Neda , Richardson Bruce 
Published: April 2014

Abstract
Why systemic lupus erythematosus primarily affects women is unknown. Recent evidence indicates that human lupus is an epigenetic disease characterized by impaired T cell DNA methylation. Women have two X chromosomes; one is inactivated by mechanisms including DNA methylation. We hypothesized that demethylation of sequences on the inactive X may cause gene overexpression uniquely in women, predisposing them to lupus. We therefore compared expression and methylation of CD40LG, a B cell costimulatory molecule encoded on the X chromosome, in experimentally demethylated T cells from men and women and in men and women with lupus. Controls included TNFSF7, a methylation-sensitive autosomal B cell costimulatory molecule known to be demethylated and overexpressed in lupus. Bisulfite sequencing revealed that CD40LG is unmethylated in men, while women have one methylated and one unmethylated gene. 5-Azacytidine, a DNA methyltransferase inhibitor, demethylated CD40LG and doubled its expression on CD4+ T cells from women but not men, while increasing TNFSF7 expression equally between sexes. Similar studies demonstrated that CD40LG demethylates in CD4+ T cells from women with lupus, and that women but not men with lupus overexpress CD40LG on CD4+ T cells, while both overexpress TNFSF7. These studies demonstrate that regulatory sequences on the inactive X chromosome demethylate in T cells from women with lupus, contributing to CD40LG overexpression uniquely in women. Demethylation of CD40LG and perhaps other genes on the inactive X may contribute to the striking female predilection of this disease.