The Experts below are selected from a list of 31593 Experts worldwide ranked by ideXlab platform
Karen Clisedwyer - One of the best experts on this subject based on the ideXlab platform.
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breast cancer cell uptake of the Inflammatory Mediator neutrophil elastase triggers an anticancer adaptive immune response
Cancer Research, 2012Co-Authors: Elizabeth A Mittendorf, Gheath Alatrash, Na Qiao, Pariya Sukhumalchandra, Lisa S St John, Anne V Philips, Haile Xiao, Mao Zhang, Kathryn Ruisaard, Karen ClisedwyerAbstract:There is little understanding of the impact of tumor-associated neutrophils (TAN) on adaptive immunity to tumors. In this study, we report the results of an investigation of the pathobiologic basis for the prognostic significance of neutrophil elastase, a serine protease found in neutrophil granules, in a model of cyclin E (CCNE)-overexpressing breast cancer. We established that neutrophil elastase was expressed by TAN within breast cancer tissues but not by breast cancer cells. Neutrophil elastase modulated killing of breast cancer cells by CTLs specific for CCNE-derived HLA-A2-restricted peptide (ILLDWLMEV). Breast cancer cells exhibited striking antigen-specific uptake of neutrophil elastase from the microenvironment that was independent of neutrophil elastase enzymatic activity. Furthermore, neutrophil elastase uptake increased expression of low molecular weight forms of CCNE and enhanced susceptibility to peptide-specific CTL lysis, suggesting that CCNE peptides are naturally presented on breast cancer cells. Taken together, our findings reveal a previously unknown mechanism of antitumor adaptive immunity that links cancer cell uptake of an Inflammatory Mediator to an effective cytolytic response against an important breast cancer antigen.
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breast cancer cell uptake of the Inflammatory Mediator neutrophil elastase triggers an anticancer adaptive immune response
Cancer Research, 2012Co-Authors: Elizabeth A Mittendorf, Gheath Alatrash, Na Qiao, Pariya Sukhumalchandra, Lisa S St John, Anne V Philips, Haile Xiao, Mao Zhang, Kathryn Ruisaard, Karen ClisedwyerAbstract:There is little understanding of the impact of tumor-associated neutrophils (TAN) on adaptive immunity to tumors. In this study, we report the results of an investigation of the pathobiological basis for the prognostic significance of neutrophil elastase (NE), a serine protease found in neutrophil granules, in a model of cyclin E-overexpressing breast cancer. We established that NE was expressed by TAN within breast cancer tissues but not by breast cancer cells. NE modulated killing of breast cancer cells by cytotoxic T lymphocytes (CTL) specific for cyclin E-derived HLA-A2 restricted peptide (ILLDWLMEV). Breast cancer cells exhibited striking antigen-specific uptake of NE from the microenvironment that was independent of NE enzymatic activity. Further, NE uptake increased expression of low molecular weight forms of cyclin E and enhanced susceptibility to peptide-specific CTL lysis, suggesting that cyclin E peptides are naturally presented on breast cancer cells. Taken together, our findings reveal a previously unknown mechanism of antitumor adaptive immunity that links cancer cell uptake of an Inflammatory Mediator to an effective cytolytic response against an important breast cancer antigen.
Robert E W Hancock - One of the best experts on this subject based on the ideXlab platform.
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host defense peptide ll 37 in synergy with Inflammatory Mediator il 1β augments immune responses by multiple pathways
Journal of Immunology, 2007Co-Authors: Neeloffer Mookherjee, Kathleen Wee, Dawn M E Bowdish, Jelena Pistolic, Linda Rehaume, Robert E W HancockAbstract:The human cathelicidin LL-37 is a cationic host defense peptide and serves as an important component of innate immunity. It has been demonstrated to be a multifunctional modulator of innate immune responses, although the mechanism(s) underlying this have not been well characterized. In this study, it was demonstrated that LL-37 synergistically enhanced the IL-1β-induced production of cytokines (IL-6, IL-10) and chemokines such as macrophage chemoattractant proteins (MCP-1, MCP-3) in human PBMC, indicating a role in enhancing certain innate immune responses. Similarly, LL-37 synergistically enhanced chemokine production in the presence of GM-CSF, but IFN-γ, IL-4, or IL-12 addition led to antagonism, indicating that the role of LL-37 in reinforcing specific immune responses is selective and restricted to particular endogenous immune Mediators. The inhibition of G protein-coupled receptors and PI3K substantially suppressed the ability of IL-1β and LL-37 to synergistically enhance the production of chemokine MCP-3. Consistent with this, the combination of IL-1β and LL-37 enhanced the activation/phosphorylation of kinase Akt and the transcription factor CREB. The role of transcription factor NF-κB was revealed through the demonstration of enhanced phosphorylation of IκBα and the consequent nuclear translocation of NF-κB subunits p50 and p65, as well as the antagonistic effects of an inhibitor of IκBα phosphorylation. These results together indicate that the human host defense peptide LL-37 can work in synergy with the endogenous Inflammatory Mediator IL-1β to enhance the induction of specific Inflammatory effectors by a complex mechanism involving multiple pathways, thus reinforcing certain innate immune responses.
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host defense peptide ll 37 in synergy with Inflammatory Mediator il 1β augments immune responses by multiple pathways
Journal of Immunology, 2007Co-Authors: Neeloffer Mookherjee, Kathleen Wee, Dawn M E Bowdish, Jelena Pistolic, Linda Rehaume, Robert E W HancockAbstract:The human cathelicidin LL-37 is a cationic host defense peptide and serves as an important component of innate immunity. It has been demonstrated to be a multifunctional modulator of innate immune responses, although the mechanism(s) underlying this have not been well characterized. In this study, it was demonstrated that LL-37 synergistically enhanced the IL-1beta-induced production of cytokines (IL-6, IL-10) and chemokines such as macrophage chemoattractant proteins (MCP-1, MCP-3) in human PBMC, indicating a role in enhancing certain innate immune responses. Similarly, LL-37 synergistically enhanced chemokine production in the presence of GM-CSF, but IFN-gamma, IL-4, or IL-12 addition led to antagonism, indicating that the role of LL-37 in reinforcing specific immune responses is selective and restricted to particular endogenous immune Mediators. The inhibition of G protein-coupled receptors and PI3K substantially suppressed the ability of IL-1beta and LL-37 to synergistically enhance the production of chemokine MCP-3. Consistent with this, the combination of IL-1beta and LL-37 enhanced the activation/phosphorylation of kinase Akt and the transcription factor CREB. The role of transcription factor NF-kappaB was revealed through the demonstration of enhanced phosphorylation of IkappaBalpha and the consequent nuclear translocation of NF-kappaB subunits p50 and p65, as well as the antagonistic effects of an inhibitor of IkappaBalpha phosphorylation. These results together indicate that the human host defense peptide LL-37 can work in synergy with the endogenous Inflammatory Mediator IL-1beta to enhance the induction of specific Inflammatory effectors by a complex mechanism involving multiple pathways, thus reinforcing certain innate immune responses.
Douglas L Mann - One of the best experts on this subject based on the ideXlab platform.
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negative inotropic effects of high mobility group box 1 protein in isolated contracting cardiac myocytes
American Journal of Physiology-heart and Circulatory Physiology, 2008Co-Authors: Hueiping Tzeng, Jinping Fan, Jesus G Vallejo, Jianwen Dong, Xiongwen Chen, Steven R Houser, Douglas L MannAbstract:High-mobility group box 1 (HMGB1) released from necrotic cells or macrophages functions as a late Inflammatory Mediator and has been shown to induce cardiovascular collapse during sepsis. Thus far,...
Leslie G Cleland - One of the best experts on this subject based on the ideXlab platform.
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effects of hypoxia on monocyte Inflammatory Mediator production dissociation between changes in cyclooxygenase 2 expression and eicosanoid synthesis
Journal of Biological Chemistry, 2017Co-Authors: Maryanne Demasi, Leslie G Cleland, Rebecca J Cookjohnson, Gillian E Caughey, Michael J JamesAbstract:Abstract Blood-derived monocytes are found at sites of inflammation as well as in solid tumors and atherosclerotic arteries. They are an abundant source of Inflammatory eicosanoids such as prostaglandin E2 (PGE2) and thromboxane A2, which are formed via arachidonic acid (AA) metabolism by cyclooxygenase-1/2 (COX-1/2). In vitro studies of Inflammatory Mediator production are conducted invariably in room air, which does not reflect the oxygen tensions found in monocyte-containing lesions, which are frequently hypoxic. In this work we examined the effects of hypoxia at levels reported in these lesions, on monocyte COX-2 expression, the related events that lead to eicosanoid synthesis, and relationships with tumor necrosis factor (TNF)-α synthesis. In fresh human monocytes exposed to hypoxia (1% O2), there was an increase in COX-2 protein compared with cells in normoxia, and this was attributable to increased transcription and mRNA stability. However, the synthesis of PGE2 and thromboxane A2 was reduced in hypoxia and did not reflect the increased level of COX-2. Monocytes prelabeled with [3H]AA followed by lipopolysaccharide stimulation in the presence of hypoxia showed a reduced release of AA compared with cells in normoxia. In addition, hypoxia resulted in decreased phosphorylation of the p44/42 mitogen-activated protein kinase and of cytosolic phospholipase A2. Hypoxia also increased TNF-α synthesis, which appeared to play a role in COX-2 expression, and the observed increase TNF-α synthesis appeared to result from reduced PGE2 synthesis. Overall, the results suggest the existence of an autocrine loop of regulation between monocyte eicosanoid and TNF-α production, which is dysregulated in hypoxia and establishes hypoxia as being an important environmental determinant of Inflammatory Mediator production.
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dietary polyunsaturated fatty acids and Inflammatory Mediator production
The American Journal of Clinical Nutrition, 2000Co-Authors: Michael J James, Robert A Gibson, Leslie G ClelandAbstract:Many antiInflammatory pharmaceutical products inhibit the production of certain eicosanoids and cytokines and it is here that possibilities exist for therapies that incorporate n-3 and n-9 dietary fatty acids. The proInflammatory eicosanoids prostaglandin E 2 (PGE 2 ) and leukotriene B 4 (LTB 4 ) are derived from the n-6 fatty acid arachidonic acid (AA), which is maintained at high cellular concentrations by the high n-6 and low n-3 polyunsaturated fatty acid content of the modern Western diet. Flaxseed oil contains the 18-carbon n-3 fatty acid α-linolenic acid, which can be converted after ingestion to the 20-carbon n-3 fatty acid eicosapentaenoic acid (EPA). Fish oils contain both 20- and 22-carbon n-3 fatty acids, EPA and docosahexaenoic acid. EPA can act as a competitive inhibitor of AA conversion to PGE 2 and LTB 4 , and decreased synthesis of one or both of these eicosanoids has been observed after inclusion of flaxseed oil or fish oil in the diet. Analogous to the effect of n-3 fatty acids, inclusion of the 20-carbon n-9 fatty acid eicosatrienoic acid in the diet also results in decreased synthesis of LTB 4 . Regarding the proInflammatory cytokines, tumor necrosis factor α and interleukin 1β, studies of healthy volunteers and rheumatoid arthritis patients have shown ≤90% inhibition of cytokine production after dietary supplementation with fish oil. Use of flaxseed oil in domestic food preparation also reduced production of these cytokines. Novel antiInflammatory therapies can be developed that take advantage of positive interactions between the dietary fats and existing or newly developed pharmaceutical products.
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dietary polyunsaturated fatty acids and Inflammatory Mediator production
The American Journal of Clinical Nutrition, 2000Co-Authors: Michael J James, Robert A Gibson, Leslie G ClelandAbstract:Many antiInflammatory pharmaceutical products inhibit the production of certain eicosanoids and cytokines and it is here that possibilities exist for therapies that incorporate n-3 and n-9 dietary fatty acids. The proInflammatory eicosanoids prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) are derived from the n-6 fatty acid arachidonic acid (AA), which is maintained at high cellular concentrations by the high n-6 and low n-3 polyunsaturated fatty acid content of the modern Western diet. Flaxseed oil contains the 18-carbon n-3 fatty acid alpha-linolenic acid, which can be converted after ingestion to the 20-carbon n-3 fatty acid eicosapentaenoic acid (EPA). Fish oils contain both 20- and 22-carbon n-3 fatty acids, EPA and docosahexaenoic acid. EPA can act as a competitive inhibitor of AA conversion to PGE(2) and LTB(4), and decreased synthesis of one or both of these eicosanoids has been observed after inclusion of flaxseed oil or fish oil in the diet. Analogous to the effect of n-3 fatty acids, inclusion of the 20-carbon n-9 fatty acid eicosatrienoic acid in the diet also results in decreased synthesis of LTB(4). Regarding the proInflammatory ctyokines, tumor necrosis factor alpha and interleukin 1beta, studies of healthy volunteers and rheumatoid arthritis patients have shown < or = 90% inhibition of cytokine production after dietary supplementation with fish oil. Use of flaxseed oil in domestic food preparation also reduced production of these cytokines. Novel antiInflammatory therapies can be developed that take advantage of positive interactions between the dietary fats and existing or newly developed pharmaceutical products.
Elizabeth A Mittendorf - One of the best experts on this subject based on the ideXlab platform.
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breast cancer cell uptake of the Inflammatory Mediator neutrophil elastase triggers an anticancer adaptive immune response
Cancer Research, 2012Co-Authors: Elizabeth A Mittendorf, Gheath Alatrash, Na Qiao, Pariya Sukhumalchandra, Lisa S St John, Anne V Philips, Haile Xiao, Mao Zhang, Kathryn Ruisaard, Karen ClisedwyerAbstract:There is little understanding of the impact of tumor-associated neutrophils (TAN) on adaptive immunity to tumors. In this study, we report the results of an investigation of the pathobiologic basis for the prognostic significance of neutrophil elastase, a serine protease found in neutrophil granules, in a model of cyclin E (CCNE)-overexpressing breast cancer. We established that neutrophil elastase was expressed by TAN within breast cancer tissues but not by breast cancer cells. Neutrophil elastase modulated killing of breast cancer cells by CTLs specific for CCNE-derived HLA-A2-restricted peptide (ILLDWLMEV). Breast cancer cells exhibited striking antigen-specific uptake of neutrophil elastase from the microenvironment that was independent of neutrophil elastase enzymatic activity. Furthermore, neutrophil elastase uptake increased expression of low molecular weight forms of CCNE and enhanced susceptibility to peptide-specific CTL lysis, suggesting that CCNE peptides are naturally presented on breast cancer cells. Taken together, our findings reveal a previously unknown mechanism of antitumor adaptive immunity that links cancer cell uptake of an Inflammatory Mediator to an effective cytolytic response against an important breast cancer antigen.
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breast cancer cell uptake of the Inflammatory Mediator neutrophil elastase triggers an anticancer adaptive immune response
Cancer Research, 2012Co-Authors: Elizabeth A Mittendorf, Gheath Alatrash, Na Qiao, Pariya Sukhumalchandra, Lisa S St John, Anne V Philips, Haile Xiao, Mao Zhang, Kathryn Ruisaard, Karen ClisedwyerAbstract:There is little understanding of the impact of tumor-associated neutrophils (TAN) on adaptive immunity to tumors. In this study, we report the results of an investigation of the pathobiological basis for the prognostic significance of neutrophil elastase (NE), a serine protease found in neutrophil granules, in a model of cyclin E-overexpressing breast cancer. We established that NE was expressed by TAN within breast cancer tissues but not by breast cancer cells. NE modulated killing of breast cancer cells by cytotoxic T lymphocytes (CTL) specific for cyclin E-derived HLA-A2 restricted peptide (ILLDWLMEV). Breast cancer cells exhibited striking antigen-specific uptake of NE from the microenvironment that was independent of NE enzymatic activity. Further, NE uptake increased expression of low molecular weight forms of cyclin E and enhanced susceptibility to peptide-specific CTL lysis, suggesting that cyclin E peptides are naturally presented on breast cancer cells. Taken together, our findings reveal a previously unknown mechanism of antitumor adaptive immunity that links cancer cell uptake of an Inflammatory Mediator to an effective cytolytic response against an important breast cancer antigen.