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https://www.readbyqxmd.com/read/27895176/the-syk-nfat-il-2-pathway-in-dendritic-cells-is-required-for-optimal-sterile-immunity-elicited-by-alum-adjuvants
#1
Hanif Javanmard Khameneh, Adrian W S Ho, Roberto Spreafico, Heidi Derks, Hazel Q Y Quek, Alessandra Mortellaro
Despite a long history and extensive usage of insoluble aluminum salts (alum) as vaccine adjuvants, the molecular mechanisms underpinning Ag-specific immunity upon vaccination remain unclear. Dendritic cells (DCs) are crucial initiators of immune responses, but little is known about the molecular pathways used by DCs to sense alum and, in turn, activate T and B cells. In this article, we show that alum adjuvanticity requires IL-2 specifically released by DCs, even when T cell secretion of IL-2 is intact. We demonstrate that alum, as well as other sterile particulates, such as uric acid crystals, induces DCs to produce IL-2 following initiation of actin-mediated phagocytosis that leads to Src and Syk kinase activation, Ca(2+) mobilization, and calcineurin-dependent activation of NFAT, the master transcription factor regulating IL-2 expression...
November 28, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27890932/il-10-production-by-cll-cells-is-enhanced-in-the-anergic-ighv-mutated-subset-and-associates-with-reduced-dna-methylation-of-the-il10-locus
#2
S Drennan, A D'Avola, Y Gao, C Weigel, E Chrysostomou, A J Steele, T Zenz, C Plass, P W Johnson, A P Williams, G Packham, F K Stevenson, C C Oakes, F Forconi
Chronic lymphocytic leukemias (CLL) with unmutated (U-CLL) or mutated (M-CLL) IGHV have variable features of immunosuppression, possibly influenced by those CLL cells activated to produce IL-10. The two subsets differ in their levels of anergy, defined by low surface IgM levels/signaling capacity, and in their DNA methylation profile, particularly variable in M-CLL. We have now found that levels of IL-10 produced by activated CLL cells were highly variable. Levels were higher in M-CLL than in U-CLL and correlated with anergy...
November 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27888629/inhibition-of-bcr-signaling-using-the-syk-inhibitor-tak-659-prevents-stroma-mediated-signaling-in-chronic-lymphocytic-leukemia-cells
#3
Noelia Purroy, Júlia Carabia, Pau Abrisqueta, Leire Egia, Meritxell Aguiló, Cecilia Carpio, Carles Palacio, Marta Crespo, Francesc Bosch
Proliferation and survival of chronic lymphocytic leukemia (CLL) cells depend on microenvironmental signals coming from lymphoid organs. One of the key players involved in the crosstalk between CLL cells and the microenvironment is the B-cell receptor (BCR). Syk protein, a tyrosine kinase essential for BCR signaling, is therefore a rational candidate for targeted therapy in CLL. Against this background, we tested the efficacy of the highly specific Syk inhibitor TAK-659 in suppressing the favorable signaling derived from the microenvironment...
November 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/27837109/characterization-of-the-syk-dependent-t-cell-signaling-response-to-an-altered-peptide
#4
Jeoung-Eun Park, Jeffrey A Rotondo, David L Cullins, David D Brand, Ae-Kyung Yi, John M Stuart, Andrew H Kang, Linda K Myers
Rheumatoid arthritis is an autoimmune disorder characterized by T cell dysregulation. We have shown that an altered peptide ligand (A9) activates T cells to use an alternate signaling pathway that is dependent on FcRγ and spleen tyrosine kinase, resulting in downregulation of inflammation. In the experiments described in this study, we have attempted to determine the molecular basis of this paradox. Three major Src family kinases found in T cells (Lck, Fyn, and Lyn) were tested for activation following stimulation by A9/I-A(q) Unexpectedly we found they are not required for T cell functions induced by A9/I-A(q), nor are they required for APL stimulation of cytokines...
December 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27756749/phosphodiesterase-4-inhibitors-have-wide-ranging-activity-in-b-cell-malignancies
#5
Jeffrey D Cooney, Ricardo C T Aguiar
Phosphodiesterase 4 (PDE4) inhibition restores the suppressive effects of cyclic-AMP in lymphocytes. In this concise review, we detail how PDE4 inhibition downmodulates the B-cell receptor (BCR)-related kinases SYK and PI3K, inhibits VEGFA secretion by tumor cells, inducing cancer cell apoptosis and blocking angiogenesis in the microenvironment. We describe the successful clinical repurposing of PDE4 inhibitors in B-cell malignancies, and propose that given their anti-inflammatory/immunomodulatory activity, these agents will suppress BCR signals without the toxicity associated with other targeted biological doublets...
October 18, 2016: Blood
https://www.readbyqxmd.com/read/27621811/phosphocholine-containing-ligands-direct-crp-induction-of-m2-macrophage-polarization-independent-of-t-cell-polarization-implication-for-chronic-inflammatory-states
#6
JoAnn Trial, Katarzyna A Cieslik, Mark L Entman
INTRODUCTION: We studied monocyte transendothelial migration and subsequent polarization into M1/M2 macrophages in response to C-reactive protein (CRP) with two disease-related ligands: (1) phosphocholine (PC) and (2) multilamellar liposomes containing both unoxidized and oxidized forms of the lipid, phosphatidylcholine. These ligands differ in biological origin: PC is present on bacterial cell walls while oxidized lipids are present in atherogenic lipids. METHODS: We used an in vitro model of human monocyte transendothelial migration and assessed the polarization of monocytes and T cells and signaling through Fcγ receptors in monocytes...
September 2016: Immunity, Inflammation and Disease
https://www.readbyqxmd.com/read/27492902/dectin-1-activated-dendritic-cells-trigger-potent-antitumour-immunity-through-the-induction-of-th9-cells
#7
Yinghua Zhao, Xiao Chu, Jintong Chen, Ying Wang, Sujun Gao, Yuxue Jiang, Xiaoqing Zhu, Guangyun Tan, Wenjie Zhao, Huanfa Yi, Honglin Xu, Xingzhe Ma, Yong Lu, Qing Yi, Siqing Wang
Dectin-1 signalling in dendritic cells (DCs) has an important role in triggering protective antifungal Th17 responses. However, whether dectin-1 directs DCs to prime antitumour Th9 cells remains unclear. Here, we show that DCs activated by dectin-1 agonists potently promote naive CD4(+) T cells to differentiate into Th9 cells. Abrogation of dectin-1 in DCs completely abolishes their Th9-polarizing capability in response to dectin-1 agonist curdlan. Notably, dectin-1 stimulation of DCs upregulates TNFSF15 and OX40L, which are essential for dectin-1-activated DC-induced Th9 cell priming...
2016: Nature Communications
https://www.readbyqxmd.com/read/27484700/mapping-epigenetic-changes-to-the-host-cell-genome-induced-by-burkholderia-pseudomallei-reveals-pathogen-specific-and-pathogen-generic-signatures-of-infection
#8
Deniz Cizmeci, Emma L Dempster, Olivia L Champion, Sariqa Wagley, Ozgur E Akman, Joann L Prior, Orkun S Soyer, Jonathan Mill, Richard W Titball
The potential for epigenetic changes in host cells following microbial infection has been widely suggested, but few examples have been reported. We assessed genome-wide patterns of DNA methylation in human macrophage-like U937 cells following infection with Burkholderia pseudomallei, an intracellular bacterial pathogen and the causative agent of human melioidosis. Our analyses revealed significant changes in host cell DNA methylation, at multiple CpG sites in the host cell genome, following infection. Infection induced differentially methylated probes (iDMPs) showing the greatest changes in DNA methylation were found to be in the vicinity of genes involved in inflammatory responses, intracellular signalling, apoptosis and pathogen-induced signalling...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27456487/fc%C3%AE-riib-independent-mechanisms-controlling-membrane-localization-of-the-inhibitory-phosphatase-ship-in-human-b-cells
#9
Samantha D Pauls, Arnab Ray, Sen Hou, Andrew T Vaughan, Mark S Cragg, Aaron J Marshall
SHIP is an important regulator of immune cell signaling that functions to dephosphorylate the phosphoinositide phosphatidylinositol 3,4,5-trisphosphate at the plasma membrane and mediate protein-protein interactions. One established paradigm for SHIP activation involves its recruitment to the phospho-ITIM motif of the inhibitory receptor FcγRIIB. Although SHIP is essential for the inhibitory function of FcγRIIB, it also has critical modulating functions in signaling initiated from activating immunoreceptors such as B cell Ag receptor...
September 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27449326/curdlan-activates-dendritic-cells-through-dectin-1-and-toll-like-receptor-4-signaling
#10
Hyung Sook Kim, Ki Hwan Park, Hong Kyung Lee, Ji Sung Kim, Yong Guk Kim, Jae Hee Lee, Ki Hun Kim, Jieun Yun, Bang Yeon Hwang, Jin Tae Hong, Youngsoo Kim, Sang-Bae Han
Curdlan, a β-1,3-glucan isolated from Alcaligenes faecalis, is an agonist of dectin-1 in various immune cells, including dendritic cells (DCs). However, whether curdlan also activates DCs through other receptors remains unknown. In this study, we found that curdlan activates DCs through dectin-1 and toll-like receptor 4 (TLR4). Curdlan increased the expression levels of surface molecules (CD40, CD80, CD86, and MHC-I/II), the production of cytokines (IL-12, IL-1β, TNF-α, and IFN-β), migration toward MIP-3β, and allogeneic T cell stimulation activity of DCs...
October 2016: International Immunopharmacology
https://www.readbyqxmd.com/read/27443285/slp76-integrates-into-the-b-cell-receptor-signaling-cascade-in-chronic-lymphocytic-leukemia-cells-and-is-associated-with-an-aggressive-disease-course
#11
Nili Dezorella, Ben-Zion Katz, Mika Shapiro, Aaron Polliack, Chava Perry, Yair Herishanu
: I In the last decade, the B-cell receptor has emerged as a pivotal stimulus in the pathogenesis of chronic lymphocytic leukemia, and a very feasible therapeutic target in this disease. B-cell receptor responsiveness in chronic lymphocytic leukemia cells is heterogeneous among patients and correlates with aggressiveness of the disease. Here we show, for the first time, that SLP76, a key scaffold protein in T-cell receptor signaling, is ectopically expressed in chronic lymphocytic leukemia cells, with variable levels among patients, and correlates positively with unmutated immunoglobulin heavy chain variable gene status and ZAP-70 expression...
December 2016: Haematologica
https://www.readbyqxmd.com/read/27384937/imaging-spatiotemporal-activities-of-zap-70-in-live-t-cells-using-a-fret-based-biosensor
#12
Kaitao Li, Xue Xiang, Jie Sun, Hai-Tao He, Jianhua Wu, Yingxiao Wang, Cheng Zhu
The zeta-chain-associated protein kinase 70 kDa (ZAP-70), a member of the spleen tyrosine kinase (Syk) family, plays an essential role in early T cell receptor (TCR) signaling. Defects in ZAP-70 lead to impaired thymocyte development and peripheral T cell activation. To better understand its activation dynamics and regulation, we visualized ZAP-70 activities in single live T cells with a Förster resonance energy transfer (FRET)-based biosensor, which was designed for probing kinase activities of the Syk family...
December 2016: Annals of Biomedical Engineering
https://www.readbyqxmd.com/read/27305912/proteomic-modulation-in-breast-tumors-after-metformin-exposure-results-from-a-window-of-opportunity-trial
#13
K Kalinsky, T Zheng, H Hibshoosh, X Du, P Mundi, J Yang, S Refice, S M Feldman, B Taback, E Connolly, K D Crew, M A Maurer, D L Hershman
PURPOSE: Reverse Phase Protein Array (RPPA) is a high-throughput antibody-based technique to assess cellular protein activity. The goal of this study was to assess protein marker changes by RPPA in tumor tissue from a pre-surgical metformin trial in women with operable breast cancer (BC). METHODS: In an open-label trial, metformin 1500-mg PO daily was administered prior to resection in 35 non-diabetic patients with stage 0-III BC, body mass index ≥25 kg/m(2)...
June 15, 2016: Clinical & Translational Oncology
https://www.readbyqxmd.com/read/27297792/integrated-mate-pair-and-rna-sequencing-identifies-novel-targetable-gene-fusions-in-peripheral-t-cell-lymphoma
#14
Rebecca L Boddicker, Gina L Razidlo, Surendra Dasari, Yu Zeng, Guangzhen Hu, Ryan A Knudson, Patricia T Greipp, Jaime I Davila, Sarah H Johnson, Julie C Porcher, James B Smadbeck, Bruce W Eckloff, Daniel D Billadeau, Paul J Kurtin, Mark A McNiven, Brian K Link, Stephen M Ansell, James R Cerhan, Yan W Asmann, George Vasmatzis, Andrew L Feldman
Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of T-cell malignancies that generally demonstrate aggressive clinical behavior, often are refractory to standard therapy, and remain significantly understudied. The most common World Health Organization subtype is PTCL, not otherwise specified (NOS), essentially a "wastebasket" category because of inadequate understanding to assign cases to a more specific diagnostic entity. Identification of novel fusion genes has contributed significantly to improving the classification, biologic understanding, and therapeutic targeting of PTCLs...
September 1, 2016: Blood
https://www.readbyqxmd.com/read/27261276/lipopolysaccharide-induced-cd300b-receptor-binding-to-toll-like-receptor-4-alters-signaling-to-drive-cytokine-responses-that-enhance-septic-shock
#15
Oliver H Voss, Yousuke Murakami, Mirna Y Pena, Ha-Na Lee, Linjie Tian, David H Margulies, Jonathan M Street, Peter S T Yuen, Chen-Feng Qi, Konrad Krzewski, John E Coligan
Receptor CD300b is implicated in regulating the immune response to bacterial infection by an unknown mechanism. Here, we identified CD300b as a lipopolysaccharide (LPS)-binding receptor and determined the mechanism underlying CD300b augmentation of septic shock. In vivo depletion and adoptive transfer studies identified CD300b-expressing macrophages as the key cell type augmenting sepsis. We showed that CD300b, and its adaptor DAP12, associated with Toll-like receptor 4 (TLR4) upon LPS binding, thereby enhancing TLR4-adaptor MyD88- and TRIF-dependent signaling that resulted in an elevated pro-inflammatory cytokine storm...
June 21, 2016: Immunity
https://www.readbyqxmd.com/read/27233983/alteration-of-the-cytokine-signature-by-various-tlr-ligands-in-different-t-cell-populations-in-mog37-50-and-mog35-55-induced-eae-in-c57bl-6-mice
#16
Corinna Steckner, Andreas Weber, Anne K Mausberg, Maximilian Heininger, Felicitas Opdenhövel, Bernd C Kieseier, Hans P Hartung, Harald H Hofstetter
Interleukin 17 (IL-17), produced by T cells, plays an important role in Multiple Sclerosis (MS) and its animal model, Experimental Autoimmune Encephalomyelitis (EAE). In contrast to IL-17-producing CD4+ T cells, the contribution of IL-17-producing CD8+ T cells (Tc17) in CNS autoimmunity has been investigated less intensively. Here we investigate the role of TC17 in EAE. We compare different T cell populations and their cytokine pattern in the MOG35-55- and MOG37-50-induced EAE. We detected a similar cytokine phenotype for both EAE models in the autoimmune process assessed at different stages...
September 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/27178629/src-syk-irak1-targeted-anti-inflammatory-action-of-torreya-nucifera-butanol-fraction-in-lipopolysaccharide-activated-raw264-7-cells
#17
Shi Hyoung Kim, Jae Gwang Park, Yong Deog Hong, Eunji Kim, Kwang-Soo Baik, Deok Hyo Yoon, Sunggyu Kim, Mi-Nam Lee, Ho Sik Rho, Song Seok Shin, Jae Youl Cho
ETHNOPHARMACOLOGICAL RELEVANCE: Seed of Torreya nucifera (L.) Siebold & Zucc is used to treat several diseases in Asia. Reports document that T. nucifera has anti-cancer, anti-inflammatory, anti-oxidative activities. In spite of numerous findings on its pharmacological effects, the understanding of the molecular inhibitory mechanisms of the plant remains to be studied. Therefore, we aimed to explore in vitro anti-inflammatory mechanisms of ethyl acetate fraction (Tn-EE-BF) prepared from the seed of T...
July 21, 2016: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/27104822/effect-of-narrow-spectrum-versus-selective-kinase-inhibitors-on-the-intestinal-proinflammatory-immune-response-in-ulcerative-colitis
#18
Paolo Biancheri, Martyn R Foster, Matthew C T Fyfe, Thomas T MacDonald, Sameer Sirohi, Yemisi Solanke, Eleanor Wood, Adele Rowley, Steve Webber, Claire A Walshe
BACKGROUND: Kinases are key mediators of inflammation, highlighting the potential of kinase inhibitors as treatments for inflammatory disorders. Selective kinase inhibitors, however, have proved disappointing, particularly in the treatment of rheumatoid arthritis and inflammatory bowel disease. Consequently, to improve efficacy, attention has turned to multikinase inhibition. METHODS: The activity of a narrow spectrum kinase inhibitor, TOP1210, has been compared with selective kinase inhibitors (BIRB-796, dasatinib and BAY-61-3606) in a range of kinase assays, inflammatory cell assays, and in inflamed biopsies from patients with ulcerative colitis (UC)...
June 2016: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/27102437/trem-2-serves-as-a-negative-immune-regulator-through-syk-pathway-in-an-il-10-dependent-manner-in-lung-cancer
#19
Yinan Yao, Hequan Li, Junjun Chen, Weiyi Xu, Guangdie Yang, Zhang Bao, Dajing Xia, Guohua Lu, Shuwen Hu, Jianying Zhou
During infection, triggering receptor expressed on myeloid cells-2 (TREM-2) restrains dendritic cells (DCs) and macrophages (MΦs) phagocytosis, as well as reduces pro-inflammatory cytokines release through DNAX-activation protein 12 (DAP12) signaling. However, the role of TREM-2 signaling in cancer has never been elucidated. In the current study, we found that TREM-2 was up-regulated on peripheral blood monocytes in tumor-bearing host. More TREM-2+DCs were detected in the lung of 3LL tumor-bearing mice. On the other hand, the level of TREM-2 on pulmonary MΦs positively correlated with the pathological staging of lung cancer...
May 17, 2016: Oncotarget
https://www.readbyqxmd.com/read/27090575/detailed-gene-dose-analysis-reveals-recurrent-focal-gene-deletions-in-pediatric-b-cell-precursor-acute-lymphoblastic-leukemia
#20
Ingegerd Ivanov Öfverholm, Anh Nhi Tran, Linda Olsson, Vasilios Zachariadis, Mats Heyman, Eva Rudd, Elisabeth Syk Lundberg, Magnus Nordenskjöld, Bertil Johansson, Ann Nordgren, Gisela Barbany
To identify copy number alterations (CNAs) in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL), array comparative genomic hybridization was performed on 50 cases; detected CNAs were validated in a cohort of 191 cases analyzed by single nucleotide polymorphism arrays. Apart from CNAs involving leukemia-associated genes, recurrent deletions targeting genes not previously implicated in BCP ALL, e.g. INIP, IRF1 and PDE4B, were identified. Deletions of the DNA repair gene INIP were exclusively found in cases with t(12;21), and deletions of SH2B3 were associated with intrachromosomal amplification of chromosome 21 (p < 0...
September 2016: Leukemia & Lymphoma
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