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Amy V Paschall - One of the best experts on this subject based on the ideXlab platform.
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irf8 expressed in t cells regulates gm csf expression to control Myeloid derived suppressor cell differentiation tum6p 955
Journal of Immunology, 2015Co-Authors: Geming Lu, Chen Feng Qi, Kankana Bardhan, Amy V Paschall, Ruihua Zhang, Liang Peng, Miriam Merad, Jianjun Yang, Tracy L McgahaAbstract:During hematopoiesis, hematopoietic stem cells differentiate into granulocytes and macrophages via a distinct differentiation program that is controlled by Myeloid lineage-specific transcription factors. Mice with a null mutation of IFN Regulatory Factor 8 (IRF8) accumulate CD11b + Gr1 + Myeloid cells that phenotypically and functionally resemble tumor-induced Myeloid-derived suppressor cells (MDSCs), indicating an essential role of IRF8 in Myeloid cell lineage differentiation. However, whether IRF8 functions intrinsically or extrinsically in regulation of Myeloid cell differentiation is not fully understood. Here we report an intriguing finding that mice with IRF8 deficiency only in Myeloid cells exhibit no abnormal Myeloid cell lineage differentiation. Instead, mice with IRF8 deficiency only in T cells exhibited MDSC accumulation. We further demonstrated that IRF8-deficient T cells exhibit elevated GM-CSF expression and secretion. Treatment of mice with GM-CSF increased MDSC accumulation, and adoptive transfer of IRF8- deficient T cells, but not GM-CSF-deficient T cells, increased MDSC accumulation in the recipient mice. Overexpression of IRF8 decreased GM-CSF in T cells. Our data determine that in addition to its intrinsic role as an apoptosis regulator in Myeloid cells, IRF8 also acts extrinsically to repress GM-CSF expression in T cells to control Myeloid cell lineage differentiation, revealing a novel mechanism of adaptive immune cell regulation of myelopoiesis in vivo.
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ifn regulatory factor 8 represses gm csf expression in t cells to affect Myeloid cell lineage differentiation
Journal of Immunology, 2015Co-Authors: Tracy L Mcgaha, Kankana Bardhan, Amy V Paschall, Ruihua Zhang, Liang Peng, Miriam Merad, Jianjun Yang, Gang Zhou, Andrew L MellorAbstract:During hematopoiesis, hematopoietic stem cells constantly differentiate into granulocytes and macrophages via a distinct differentiation program that is tightly controlled by Myeloid lineage-specific transcription factors. Mice with a null mutation of IFN regulatory factor 8 (IRF8) accumulate CD11b + Gr1 + Myeloid cells that phenotypically and functionally resemble tumor-induced Myeloid-derived suppressor cells (MDSCs), indicating an essential role of IRF8 in Myeloid cell lineage differentiation. However, IRF8 is expressed in various types of immune cells, and whether IRF8 functions intrinsically or extrinsically in regulation of Myeloid cell lineage differentiation is not fully understood. In this study, we report an intriguing finding that, although IRF8-deficient mice exhibit deregulated Myeloid cell differentiation and resultant accumulation of CD11b + Gr1 + MDSCs, surprisingly, mice with IRF8 deficiency only in Myeloid cells exhibit no abnormal Myeloid cell lineage differentiation. Instead, mice with IRF8 deficiency only in T cells exhibited deregulated Myeloid cell differentiation and MDSC accumulation. We further demonstrated that IRF8-deficient T cells exhibit elevated GM-CSF expression and secretion. Treatment of mice with GM-CSF increased MDSC accumulation, and adoptive transfer of IRF8-deficient T cells, but not GM-CSF–deficient T cells, increased MDSC accumulation in the recipient chimeric mice. Moreover, overexpression of IRF8 decreased GM-CSF expression in T cells. Our data determine that, in addition to its intrinsic function as an apoptosis regulator in Myeloid cells, IRF8 also acts extrinsically to repress GM-CSF expression in T cells to control Myeloid cell lineage differentiation, revealing a novel mechanism that the adaptive immune component of the immune system regulates the innate immune cell myelopoiesis in vivo.
Karin E. Bornfeldt - One of the best experts on this subject based on the ideXlab platform.
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Myeloid cell prostaglandin e2 receptor ep4 modulates cytokine production but not atherogenesis in a mouse model of type 1 diabetes
PLOS ONE, 2016Co-Authors: Sara N. Vallerie, Katrin I Andreasson, Farah Kramer, Jenny E. Kanter, Shelley Barnhart, Richard M. Breyer, Karin E. BornfeldtAbstract:Type 1 diabetes mellitus (T1DM) is associated with cardiovascular complications induced by atherosclerosis. Prostaglandin E2 (PGE2) is often raised in states of inflammation, including diabetes, and regulates inflammatory processes. In Myeloid cells, a key cell type in atherosclerosis, PGE2 acts predominately through its Prostaglandin E Receptor 4 (EP4; Ptger4) to modulate inflammation. The effect of PGE2-mediated EP4 signaling specifically in Myeloid cells on atherosclerosis in the presence and absence of diabetes is unknown. Because diabetes promotes atherosclerosis through increased arterial Myeloid cell accumulation, we generated a Myeloid cell-targeted EP4-deficient mouse model (EP4M-/-) of T1DM-accelerated atherogenesis to investigate the relationship between Myeloid cell EP4, inflammatory phenotypes of Myeloid cells, and atherogenesis. Diabetic mice exhibited elevated plasma PGE metabolite levels and elevated Ptger4 mRNA in macrophages, as compared with non-diabetic littermates. PGE2 increased Il6, Il1b, Il23 and Ccr7 mRNA while reducing Tnfa mRNA through EP4 in isolated Myeloid cells. Consistently, the stimulatory effect of diabetes on peritoneal macrophage Il6 was mediated by PGE2-EP4, while PGE2-EP4 suppressed the effect of diabetes on Tnfa in these cells. In addition, diabetes exerted effects independent of Myeloid cell EP4, including a reduction in macrophage Ccr7 levels and increased early atherogenesis characterized by relative lesional macrophage accumulation. These studies suggest that this mouse model of T1DM is associated with increased Myeloid cell PGE2-EP4 signaling, which is required for the stimulatory effect of diabetes on IL-6, markedly blunts the effect of diabetes on TNF-α and does not modulate diabetes-accelerated atherogenesis.
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abstract 590 loss of Myeloid cell prostaglandin e receptor 4 does not alter diabetes accelerated atherosclerosis in a murine model of type 1 diabetes
Arteriosclerosis Thrombosis and Vascular Biology, 2015Co-Authors: Sara N. Vallerie, Katrin I Andreasson, Farah Kramer, Jenny E. Kanter, Shelley Barnhart, Richard M. Breyer, Karin E. BornfeldtAbstract:Diabetes is associated with an increased risk of cardiovascular disease, largely due to increased atherosclerosis. Our studies have suggested Myeloid cell prostaglandin E2 (PGE2) production as a possible mediator of diabetes-accelerated atherosclerosis in a virally-induced mouse model of type 1 diabetes. Prostaglandin E Receptor 4 (EP4; Ptger4) is a major PGE2 receptor in Myeloid cells. We hypothesized that generation of a mouse model of Myeloid cell-targeted EP4-deficiency would allow us to test the role of Myeloid EP4 in diabetes-accelerated atherosclerosis. Thus, we generated a Ptger4flox/flox LysM-Cretg/tg mouse model. Peritoneal macrophages isolated from these Myeloid cell EP4-deficient (EP4M-/-) mice expressed <90% Ptger4 mRNA compared to LysM-Cretg/tg controls (n=10; p<0.0001). To analyze the role of Myeloid cell EP4 in diabetes-accelerated atherosclerosis, we transplanted bone marrow from EP4M-/- mice and littermate controls into lethally irradiated Ldlr-/- RIP-LCMV mice (the model of type 1 diabe...
Tracy L Mcgaha - One of the best experts on this subject based on the ideXlab platform.
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irf8 expressed in t cells regulates gm csf expression to control Myeloid derived suppressor cell differentiation tum6p 955
Journal of Immunology, 2015Co-Authors: Geming Lu, Chen Feng Qi, Kankana Bardhan, Amy V Paschall, Ruihua Zhang, Liang Peng, Miriam Merad, Jianjun Yang, Tracy L McgahaAbstract:During hematopoiesis, hematopoietic stem cells differentiate into granulocytes and macrophages via a distinct differentiation program that is controlled by Myeloid lineage-specific transcription factors. Mice with a null mutation of IFN Regulatory Factor 8 (IRF8) accumulate CD11b + Gr1 + Myeloid cells that phenotypically and functionally resemble tumor-induced Myeloid-derived suppressor cells (MDSCs), indicating an essential role of IRF8 in Myeloid cell lineage differentiation. However, whether IRF8 functions intrinsically or extrinsically in regulation of Myeloid cell differentiation is not fully understood. Here we report an intriguing finding that mice with IRF8 deficiency only in Myeloid cells exhibit no abnormal Myeloid cell lineage differentiation. Instead, mice with IRF8 deficiency only in T cells exhibited MDSC accumulation. We further demonstrated that IRF8-deficient T cells exhibit elevated GM-CSF expression and secretion. Treatment of mice with GM-CSF increased MDSC accumulation, and adoptive transfer of IRF8- deficient T cells, but not GM-CSF-deficient T cells, increased MDSC accumulation in the recipient mice. Overexpression of IRF8 decreased GM-CSF in T cells. Our data determine that in addition to its intrinsic role as an apoptosis regulator in Myeloid cells, IRF8 also acts extrinsically to repress GM-CSF expression in T cells to control Myeloid cell lineage differentiation, revealing a novel mechanism of adaptive immune cell regulation of myelopoiesis in vivo.
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ifn regulatory factor 8 represses gm csf expression in t cells to affect Myeloid cell lineage differentiation
Journal of Immunology, 2015Co-Authors: Tracy L Mcgaha, Kankana Bardhan, Amy V Paschall, Ruihua Zhang, Liang Peng, Miriam Merad, Jianjun Yang, Gang Zhou, Andrew L MellorAbstract:During hematopoiesis, hematopoietic stem cells constantly differentiate into granulocytes and macrophages via a distinct differentiation program that is tightly controlled by Myeloid lineage-specific transcription factors. Mice with a null mutation of IFN regulatory factor 8 (IRF8) accumulate CD11b + Gr1 + Myeloid cells that phenotypically and functionally resemble tumor-induced Myeloid-derived suppressor cells (MDSCs), indicating an essential role of IRF8 in Myeloid cell lineage differentiation. However, IRF8 is expressed in various types of immune cells, and whether IRF8 functions intrinsically or extrinsically in regulation of Myeloid cell lineage differentiation is not fully understood. In this study, we report an intriguing finding that, although IRF8-deficient mice exhibit deregulated Myeloid cell differentiation and resultant accumulation of CD11b + Gr1 + MDSCs, surprisingly, mice with IRF8 deficiency only in Myeloid cells exhibit no abnormal Myeloid cell lineage differentiation. Instead, mice with IRF8 deficiency only in T cells exhibited deregulated Myeloid cell differentiation and MDSC accumulation. We further demonstrated that IRF8-deficient T cells exhibit elevated GM-CSF expression and secretion. Treatment of mice with GM-CSF increased MDSC accumulation, and adoptive transfer of IRF8-deficient T cells, but not GM-CSF–deficient T cells, increased MDSC accumulation in the recipient chimeric mice. Moreover, overexpression of IRF8 decreased GM-CSF expression in T cells. Our data determine that, in addition to its intrinsic function as an apoptosis regulator in Myeloid cells, IRF8 also acts extrinsically to repress GM-CSF expression in T cells to control Myeloid cell lineage differentiation, revealing a novel mechanism that the adaptive immune component of the immune system regulates the innate immune cell myelopoiesis in vivo.
Sara N. Vallerie - One of the best experts on this subject based on the ideXlab platform.
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Myeloid cell prostaglandin e2 receptor ep4 modulates cytokine production but not atherogenesis in a mouse model of type 1 diabetes
PLOS ONE, 2016Co-Authors: Sara N. Vallerie, Katrin I Andreasson, Farah Kramer, Jenny E. Kanter, Shelley Barnhart, Richard M. Breyer, Karin E. BornfeldtAbstract:Type 1 diabetes mellitus (T1DM) is associated with cardiovascular complications induced by atherosclerosis. Prostaglandin E2 (PGE2) is often raised in states of inflammation, including diabetes, and regulates inflammatory processes. In Myeloid cells, a key cell type in atherosclerosis, PGE2 acts predominately through its Prostaglandin E Receptor 4 (EP4; Ptger4) to modulate inflammation. The effect of PGE2-mediated EP4 signaling specifically in Myeloid cells on atherosclerosis in the presence and absence of diabetes is unknown. Because diabetes promotes atherosclerosis through increased arterial Myeloid cell accumulation, we generated a Myeloid cell-targeted EP4-deficient mouse model (EP4M-/-) of T1DM-accelerated atherogenesis to investigate the relationship between Myeloid cell EP4, inflammatory phenotypes of Myeloid cells, and atherogenesis. Diabetic mice exhibited elevated plasma PGE metabolite levels and elevated Ptger4 mRNA in macrophages, as compared with non-diabetic littermates. PGE2 increased Il6, Il1b, Il23 and Ccr7 mRNA while reducing Tnfa mRNA through EP4 in isolated Myeloid cells. Consistently, the stimulatory effect of diabetes on peritoneal macrophage Il6 was mediated by PGE2-EP4, while PGE2-EP4 suppressed the effect of diabetes on Tnfa in these cells. In addition, diabetes exerted effects independent of Myeloid cell EP4, including a reduction in macrophage Ccr7 levels and increased early atherogenesis characterized by relative lesional macrophage accumulation. These studies suggest that this mouse model of T1DM is associated with increased Myeloid cell PGE2-EP4 signaling, which is required for the stimulatory effect of diabetes on IL-6, markedly blunts the effect of diabetes on TNF-α and does not modulate diabetes-accelerated atherogenesis.
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abstract 590 loss of Myeloid cell prostaglandin e receptor 4 does not alter diabetes accelerated atherosclerosis in a murine model of type 1 diabetes
Arteriosclerosis Thrombosis and Vascular Biology, 2015Co-Authors: Sara N. Vallerie, Katrin I Andreasson, Farah Kramer, Jenny E. Kanter, Shelley Barnhart, Richard M. Breyer, Karin E. BornfeldtAbstract:Diabetes is associated with an increased risk of cardiovascular disease, largely due to increased atherosclerosis. Our studies have suggested Myeloid cell prostaglandin E2 (PGE2) production as a possible mediator of diabetes-accelerated atherosclerosis in a virally-induced mouse model of type 1 diabetes. Prostaglandin E Receptor 4 (EP4; Ptger4) is a major PGE2 receptor in Myeloid cells. We hypothesized that generation of a mouse model of Myeloid cell-targeted EP4-deficiency would allow us to test the role of Myeloid EP4 in diabetes-accelerated atherosclerosis. Thus, we generated a Ptger4flox/flox LysM-Cretg/tg mouse model. Peritoneal macrophages isolated from these Myeloid cell EP4-deficient (EP4M-/-) mice expressed <90% Ptger4 mRNA compared to LysM-Cretg/tg controls (n=10; p<0.0001). To analyze the role of Myeloid cell EP4 in diabetes-accelerated atherosclerosis, we transplanted bone marrow from EP4M-/- mice and littermate controls into lethally irradiated Ldlr-/- RIP-LCMV mice (the model of type 1 diabe...
Feixiong Cheng - One of the best experts on this subject based on the ideXlab platform.
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pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute Myeloid leukemia cells
Haematologica, 2018Co-Authors: Wanyan Wang, Wuyan Chen, Fulin Lian, Li Lang, Ying Huang, Naixia Zhang, Yinbin Chen, Mingyao Liu, Ruth Nussinov, Feixiong ChengAbstract:Acute Myeloid leukemia is a disorder characterized by abnormal differentiation of Myeloid cells and a clonal proliferation derived from primitive hematopoietic stem cells. Interventions that overcome Myeloid differentiation have been shown to be a promising therapeutic strategy for acute Myeloid leukemia. In this study, we demonstrate that CRISPR/Cas9-mediated knockout of dihydroorotate dehydrogenase leads to apoptosis and normal differentiation of acute Myeloid leukemia cells, indicating that dihydroorotate dehydrogenase is a potential differentiation regulator and a therapeutic target in acute Myeloid leukemia. By screening a library of natural products, we identified a novel dihydroorotate dehydrogenase inhibitor, isobavachalcone, derived from the traditional Chinese medicine Psoralea corylifolia. Using enzymatic analysis, thermal shift assay, pull down, nuclear magnetic resonance, and isothermal titration calorimetry experiments, we demonstrate that isobavachalcone inhibits human dihydroorotate dehydrogenase directly, and triggers apoptosis and differentiation of acute Myeloid leukemia cells. Oral administration of isobavachalcone suppresses subcutaneous HL60 xenograft tumor growth without obvious toxicity. Importantly, our results suggest that a combination of isobavachalcone and adriamycin prolonged survival in an intravenous HL60 leukemia model. In summary, this study demonstrates that isobavachalcone triggers apoptosis and differentiation of acute Myeloid leukemia cells via pharmacological inhibition of human dihydroorotate dehydrogenase, offering a potential therapeutic strategy for acute Myeloid leukemia.