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Bortezomib augments lymphocyte stimulatory cytokine signaling in the tumor microenvironment to sustain CD8+T cell antitumor function.
Pellom ST, Dudimah DF, Thounaojam MC, Uzhachenko RV, Singhal A, Richmond A, Shanker A
(2017) Oncotarget 8: 8604-8621
MeSH Terms: Adenocarcinoma, Animals, Antineoplastic Agents, Bortezomib, Breast Neoplasms, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Cytokines, Female, Fibrosarcoma, Kidney Neoplasms, Lung Neoplasms, Lymphocytes, Tumor-Infiltrating, Mice, Inbred BALB C, Mice, Transgenic, Phosphatidylinositol 3-Kinase, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Proto-Oncogene Proteins c-akt, Receptors, Cytokine, STAT5 Transcription Factor, Signal Transduction, Tumor Escape, Tumor Microenvironment
Show Abstract · Added March 14, 2017
Tumor-induced immune tolerance poses a major challenge for therapeutic interventions aimed to manage cancer. We explored approaches to overcome T-cell suppression in murine breast and kidney adenocarcinomas, and lung fibrosarcoma expressing immunogenic antigens. We observed that treatment with a reversible proteasome inhibitor bortezomib (1 mg/kg body weight) in tumor-bearing mice significantly enhanced the expression of lymphocyte-stimulatory cytokines IL-2, IL-12, and IL-15. Notably, bortezomib administration reduced pulmonary nodules of mammary adenocarcinoma 4T1.2 expressing hemagglutinin (HA) model antigen (4T1HA) in mice. Neutralization of IL-12 and IL-15 cytokines with a regimen of blocking antibodies pre- and post-adoptive transfer of low-avidity HA518-526-specific CD8+T-cells following intravenous injection of 4T1HA cells increased the number of pulmonary tumor nodules. This neutralization effect was counteracted by the tumor metastasis-suppressing action of bortezomib treatments. In bortezomib-treated 4T1HA tumor-bearing mice, CD4+T-cells showed increased IL-2 production, CD11c+ dendritic cells showed increased IL-12 and IL-15 production, and HA-specific activated CD8+T-cells showed enhanced expression of IFNγ, granzyme-B and transcription factor eomesodermin. We also noted a trend of increased expression of IL-2, IL-12 and IL-15 receptors as well as increased phosphorylation of STAT5 in tumor-infiltrating CD8+T-cells following bortezomib treatment. Furthermore, bortezomib-treated CD8+T-cells showed increased phosphorylation of mitogen-activated protein kinase p38, and Akt, which was abrogated by phosphatidylinositide 3-kinase (PI3K) inhibitor. These data support the therapeutic potential of bortezomib in conjunction with other immunotherapies to augment the strength of convergent signals from CD8+T-cell signaling molecules including TCR, cytokine receptors and downstream PI3K/Akt/STAT5 pathways to sustain CD8+T-cell effector function in the tumor microenvironment.
2 Communities
1 Members
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24 MeSH Terms
Inflammatory cytokine TSLP stimulates platelet secretion and potentiates platelet aggregation via a TSLPR-dependent PI3K/Akt signaling pathway.
Dong J, Dong J, Lin J, Wang B, He S, Wu C, Kushwaha KK, Mohabeer N, Su Y, Fang H, Huang K, Li D
(2015) Cell Physiol Biochem 35: 160-74
MeSH Terms: Androstadienes, Animals, Blood Platelets, Carotid Artery Thrombosis, Chlorides, Chromones, Cytokines, Disease Models, Animal, Ferric Compounds, Humans, Immunoglobulins, Mice, Mice, Inbred C57BL, Mice, Knockout, Morpholines, P-Selectin, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation, Platelet Activation, Platelet Aggregation, Platelet Glycoprotein GPIIb-IIIa Complex, Proto-Oncogene Proteins c-akt, Receptors, Cytokine, Signal Transduction, Wortmannin
Show Abstract · Added January 20, 2015
AIMS - Thymic stromal lymphopoietin (TSLP) plays an important role in inflammatory diseases and is over-expressed in human atherosclerotic artery specimens. The present study investigated the role of TSLP in platelet activation and thrombosis models in vitro and in vivo, as well as the underlying mechanism and signaling pathway.
METHODS AND RESULTS - Western blotting and flow cytometry demonstrated that the TSLP receptor was expressed on murine platelets. According to flow cytometry, platelet stimulation with TSLP induced platelet degranulation and integrin αIIbβ3 activation. A TSLPR deficiency caused defective platelet aggregation, defective platelet secretion and markedly blunted thrombus growth in perfusion chambers at both low and high shear rates. TSLPR KO mice exhibited defective carotid artery thrombus formation after exposure to FeCl3. TSLP increased Akt phosphorylation, an effect that was abrogated by the PI3K inhibitors wortmannin and LY294002. The PI3K inhibitors further diminished TSLP-induced platelet activation. TSLP-mediated platelet degranulation, integrin αIIbβ3 activation and Akt phosphorylation were blunted in platelets that lacked the TSLP receptor.
CONCLUSION - This study demonstrated that the functional TSLPR was surface-expressed on murine platelets. The inflammatory cytokine TSLP triggered platelet activation and thrombus formation via TSLP-dependent PI3K/Akt signaling, which suggests an important role for TSLP in linking vascular inflammation and thrombo-occlusive diseases.
© 2015 S. Karger AG, Basel.
0 Communities
1 Members
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26 MeSH Terms
An evidence-based knowledgebase of pulmonary arterial hypertension to identify genes and pathways relevant to pathogenesis.
Zhao M, Austin ED, Hemnes AR, Loyd JE, Zhao Z
(2014) Mol Biosyst 10: 732-40
MeSH Terms: Chromosome Mapping, Data Collection, Databases, Genetic, Familial Primary Pulmonary Hypertension, Focal Adhesions, Humans, Internet, MAP Kinase Signaling System, Neoplasms, Receptors, Cytokine, Transforming Growth Factor beta
Show Abstract · Added March 11, 2014
Pulmonary arterial hypertension (PAH) is a major progressive form of pulmonary hypertension (PH) with more than 4800 patients in the United States. In the last two decades, many studies have identified numerous genes associated with this disease. However, there is no comprehensive research resource for PAH or other PH types that integrates various genetic studies and their related biological information. Thus, the number of associated genes, and their strength of evidence, is unclear. In this study, we tested the hypothesis that a web-based knowledgebase could be used to develop a biological map of highly interrelated, functionally important genes in PAH. We developed the pulmonary arterial hypertension knowledgebase (PAHKB, ), a comprehensive database with a user-friendly web interface. PAHKB extracts genetic data from all available sources, including those from association studies, genetic mutation, gene expression, animal model, supporting literature, various genomic annotations, gene networks, cellular and regulatory pathways, as well as microRNAs. Moreover, PAHKB provides online tools for data browsing and searching, data integration, pathway graphical presentation, and gene ranking. In the current release, PAHKB contains 341 human PH-related genes (293 protein coding and 48 non-coding genes) curated from over 1000 PubMed abstracts. Based on the top 39 ranked PAH-related genes in PAHKB, we constructed a core biological map. This core map was enriched with the TGF-beta signaling pathway, focal adhesion, cytokine-cytokine receptor interaction, and MAPK signaling. In addition, the reconstructed map elucidates several novel cancer signaling pathways, which may provide clues to support the application of anti-cancer therapeutics to PAH. In summary, we have developed a system for the identification of core PH-related genes and identified critical signaling pathways that may be relevant to PAH pathogenesis. This system can be easily applied to other pulmonary diseases.
0 Communities
3 Members
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11 MeSH Terms
Organ-specific features of natural killer cells.
Shi FD, Ljunggren HG, La Cava A, Van Kaer L
(2011) Nat Rev Immunol 11: 658-71
MeSH Terms: Animals, Autoimmunity, Brain, Cell Communication, Cytokines, Cytotoxicity, Immunologic, Disease Models, Animal, Female, Humans, Inflammation, Intestinal Mucosa, Joints, Killer Cells, Natural, Liver, Mice, Mice, Transgenic, Organ Specificity, Pancreas, Receptors, Antigen, T-Cell, Receptors, Cytokine, Signal Transduction, Uterus
Show Abstract · Added March 20, 2014
Natural killer (NK) cells can be swiftly mobilized by danger signals and are among the earliest arrivals at target organs of disease. However, the role of NK cells in mounting inflammatory responses is often complex and sometimes paradoxical. Here, we examine the divergent phenotypic and functional features of NK cells, as deduced largely from experimental mouse models of pathophysiological responses in the liver, mucosal tissues, uterus, pancreas, joints and brain. Moreover, we discuss how organ-specific factors, the local microenvironment and unique cellular interactions may influence the organ-specific properties of NK cells.
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1 Members
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22 MeSH Terms
The inhibitory cytokine IL-35 contributes to regulatory T-cell function.
Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, Cross R, Sehy D, Blumberg RS, Vignali DA
(2007) Nature 450: 566-9
MeSH Terms: Animals, Cell Line, Cell Proliferation, Disease Models, Animal, Flow Cytometry, Forkhead Transcription Factors, Gene Expression Regulation, Humans, Inflammatory Bowel Diseases, Interleukin-12 Subunit p35, Mice, Mice, Inbred C57BL, Minor Histocompatibility Antigens, Receptors, Cytokine, T-Lymphocytes, Regulatory
Show Abstract · Added March 5, 2014
Regulatory T (T(reg)) cells are a critical sub-population of CD4+ T cells that are essential for maintaining self tolerance and preventing autoimmunity, for limiting chronic inflammatory diseases, such as asthma and inflammatory bowel disease, and for regulating homeostatic lymphocyte expansion. However, they also suppress natural immune responses to parasites and viruses as well as anti-tumour immunity induced by therapeutic vaccines. Although the manipulation of T(reg) function is an important goal of immunotherapy, the molecules that mediate their suppressive activity remain largely unknown. Here we demonstrate that Epstein-Barr-virus-induced gene 3 (Ebi3, which encodes IL-27beta) and interleukin-12 alpha (Il12a, which encodes IL-12alpha/p35) are highly expressed by mouse Foxp3+ (forkhead box P3) T(reg) cells but not by resting or activated effector CD4+ T (T(eff)) cells, and that an Ebi3-IL-12alpha heterodimer is constitutively secreted by T(reg) but not T(eff) cells. Both Ebi3 and Il12a messenger RNA are markedly upregulated in T(reg) cells co-cultured with T(eff) cells, thereby boosting Ebi3 and IL-12alpha production in trans. T(reg)-cell restriction of this cytokine occurs because Ebi3 is a downstream target of Foxp3, a transcription factor that is required for T(reg)-cell development and function. Ebi3-/- and Il12a-/- T(reg) cells have significantly reduced regulatory activity in vitro and fail to control homeostatic proliferation and to cure inflammatory bowel disease in vivo. Because these phenotypic characteristics are distinct from those of other IL-12 family members, this novel Ebi3-IL-12alpha heterodimeric cytokine has been designated interleukin-35 (IL-35). Ectopic expression of IL-35 confers regulatory activity on naive T cells, whereas recombinant IL-35 suppresses T-cell proliferation. Taken together, these data identify IL-35 as a novel inhibitory cytokine that may be specifically produced by T(reg) cells and is required for maximal suppressive activity.
0 Communities
1 Members
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15 MeSH Terms
Gender-specific differences in expression in human lymphoblastoid cell lines.
Zhang W, Bleibel WK, Roe CA, Cox NJ, Eileen Dolan M
(2007) Pharmacogenet Genomics 17: 447-50
MeSH Terms: Adherens Junctions, Cell Line, Databases, Genetic, Female, Gene Expression, Gene Expression Profiling, Genetic Predisposition to Disease, Humans, Lymphocytes, Male, Oligonucleotide Array Sequence Analysis, Receptors, Cytokine, Sex Characteristics
Show Abstract · Added February 22, 2016
Women and men have different risks for certain diseases and they often respond differently to treatment. These differences could be due to the sex-specific differences in the expression of genes related to primary disease susceptibility or pharmacodynamic targets. To evaluate the sex-specific pattern of gene expression, we compared gene expression levels using a publicly available microarray dataset of 233 (115 women and 118 men) lymphoblastoid cell lines. From the 4799 probes meeting a specified minimal level of expression, 10 genes (P<0.005, permutation adjusted false discovery rate less than 50%) located on autosomal chromosomes were identified using a permutation-based approach. These genes were found to be over-represented in certain gene ontology terms of biological process (cell adhesion, apoptosis, transcription and signal transduction), and molecular function (structural molecule activity, zinc ion binding, transcription factor activity and protein binding). A Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that two known pathways are over-represented: adherens junction and cytokine-cytokine receptor interaction.
0 Communities
1 Members
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13 MeSH Terms
Quantum dot probes for monitoring dynamic cellular response: reporters of T cell activation.
Warnement MR, Faley SL, Wikswo JP, Rosenthal SJ
(2006) IEEE Trans Nanobioscience 5: 268-72
MeSH Terms: Cytokines, Humans, Jurkat Cells, Lymphocyte Activation, Microscopy, Fluorescence, Molecular Probe Techniques, Quantum Dots, Receptors, Cytokine, T-Lymphocytes
Show Abstract · Added May 27, 2014
Antibody-conjugated quantum dots (QDs) have been used to map the expression dynamics of the cytokine receptor interleukin-2 receptor-alpha (IL-2Ralpha) following Jurkat T cell activation. Maximal receptor expression was observed 48 h after activation, followed by a sharp decrease consistent with IL-2R internalization subsequent to IL-2 engagement. Verification of T cell activation and specificity of QD labeling were demonstrated using fluorescence microscopy, ELISA, and FACS analyses. These antibody conjugates provide a versatile means to rapidly determine cell state and interrogate membrane associated proteins involved in cell signaling pathways. Ultimately, incorporation with a microfluidic platform capable of simultaneously monitoring several cell signaling pathways will aid in toxin detection and discrimination.
0 Communities
2 Members
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9 MeSH Terms
Highly conserved gene expression profiles in humans with allergic rhinitis altered by immunotherapy.
Liu Z, Yelverton RW, Kraft B, Tanner SB, Olsen NJ, Aune TM
(2005) Clin Exp Allergy 35: 1581-90
MeSH Terms: Adult, Chemokines, Conserved Sequence, Cytokines, Female, Gene Expression Profiling, Gene Expression Regulation, Genes, Immunoglobulin, Humans, Immunotherapy, Leukocytes, Mononuclear, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Receptors, Cytokine, Regression Analysis, Rhinitis, Allergic, Perennial, Time Factors
Show Abstract · Added December 10, 2013
BACKGROUND - Atopic diseases, resulting from hypersensitivity to a wide variety of allergens, affect 10-20% of the population. Immunotherapy is an effective treatment for atopic diseases, but its mechanisms are not fully understood.
OBJECTIVE - We studied gene expression profiles in the peripheral blood mononuclear cells (PBMC) and examined whether the individuals with allergic rhinitis (AR) have a unique gene expression profile and how the immunotherapy affect the gene expression profiles.
METHODS - We used cDNA microarray and 'expression analysis systemic explorer' to examine the gene expression profiles in the PBMC of atopic subjects and other groups.
RESULTS - We identified a highly conserved gene expression profile in atopic subjects that permitted their accurate segregation from control or autoimmune subjects. A major feature of this profile was the under-expression of a variety of genes that encode proteins required for apoptosis and over-expression of genes that encode proteins critical for stress responses and signal transduction. We also identified 563 genes that can segregate individuals with AR based upon receipt of immunotherapy.
CONCLUSION - There is a highly conserved gene expression profile in the PBMC of individuals with AR. This profile can be used to identify individuals with AR and to evaluate responses to immunotherapy. Quantitative endpoints, such as gene expression, may assist clinicians faced with clinical decisions in the diagnosis of patients and the evaluation of response to therapy. The knowledge of the possible genetic basis for immunotherapy efficacy may also lead to novel therapeutic approaches for atopic diseases.
0 Communities
2 Members
0 Resources
18 MeSH Terms
Targeting cytokine receptors and pathways in the treatment of breast cancer.
Mayer IA
(2005) Cancer Treat Res 126: 243-62
MeSH Terms: Animals, Anticarcinogenic Agents, Breast Neoplasms, Humans, Receptors, Cytokine
Added March 5, 2014
0 Communities
1 Members
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5 MeSH Terms
Analysis of gamma c-family cytokine target genes. Identification of dual-specificity phosphatase 5 (DUSP5) as a regulator of mitogen-activated protein kinase activity in interleukin-2 signaling.
Kovanen PE, Rosenwald A, Fu J, Hurt EM, Lam LT, Giltnane JM, Wright G, Staudt LM, Leonard WJ
(2003) J Biol Chem 278: 5205-13
MeSH Terms: Cells, Cultured, Dual-Specificity Phosphatases, Gene Expression Regulation, Humans, Interleukin-2, MAP Kinase Signaling System, Protein Tyrosine Phosphatases, Receptors, Cytokine, Signal Transduction, T-Lymphocytes
Show Abstract · Added March 5, 2014
Interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 form a family of cytokines based on their sharing the common cytokine receptor gamma chain, gamma(c), which is mutated in X-linked severe combined immunodeficiency (SCID). As a step toward further elucidating the mechanism of action of these cytokines in T-cell biology, we compared the gene expression profiles of IL-2, IL-4, IL-7, and IL-15 in T cells using cDNA microarrays. IL-2, IL-7, and IL-15 each induced a highly similar set of genes, whereas IL-4 induced distinct genes correlating with differential STAT protein activation by this cytokine. One gene induced by IL-2, IL-7, and IL-15 but not IL-4 was dual-specificity phosphatase 5 (DUSP5). In IL-2-dependent CTLL-2 cells, we show that IL-2-induced ERK-1/2 activity was inhibited by wild type DUSP5 but markedly increased by an inactive form of DUSP5, suggesting a negative feedback role for DUSP5 in IL-2 signaling. Our findings provide insights into the shared versus distinctive actions by different members of the gamma(c) family of cytokines. Moreover, we have identified a DUSP5-dependent negative regulatory pathway for MAPK activity in T cells.
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10 MeSH Terms