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Yanmei Wang - One of the best experts on this subject based on the ideXlab platform.
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il 27 inhibits hiv 1 infection in human Macrophages by down regulating host factor sptbn1 during monocyte to Macrophage Differentiation
Cytokine, 2013Co-Authors: Kristy B Lidie, Tauseef Rehman, Robert Laurie Dewar, Joseph W Adelsberger, Dawei Huang, Richard A. Lempicki, Xin Zheng, Qian Chen, Yanmei WangAbstract:Macrophages represent a major target and viral reservoir of HIV-1 infection. The susceptibility of Macrophages to HIV-1 infection is modulated during monocyte Differentiation. IL-27 is an antiviral cytokine which also plays a role in monocyte activation. Here, we present new evidence that IL-27 promotes monocyte Differentiation into Macrophages that are non-permissive for HIV-1 infection. While IL-27 treatment does not affect expression of Macrophage Differentiation markers or Macrophage biological functions, it confers HIV resistance by down-regulating SPTBN1, a required host factor for HIV-1 infection. IL-27 down-regulates SPTBN1 during monocyte Differentiation through a TAK-1-mediated MAPK signaling pathway. Knockdown of SPTBN1 strongly inhibits HIV-1 infection of Macrophages; conversely, overexpression of SPTBN1 markedly increases HIV susceptibility of IL-27 treated Macrophages. Moreover, we demonstrate that SPTBN1 associates with HIV-1 gag proteins. Collectively, our results underscore the ability of IL-27 to protect Macrophages from HIV-1 infection by down-regulating SPTBN1 during monocyte to Macrophage Differentiation without altering other Macrophage biological functions, thus indicating IL-27 as a potential immunotherapeutic reagent to prevent HIV-1 infection.
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il 27 inhibits hiv 1 infection in human Macrophages by down regulating host factor sptbn1 during monocyte to Macrophage Differentiation
Journal of Experimental Medicine, 2013Co-Authors: Kristy B Lidie, Tauseef Rehman, Robert Laurie Dewar, Joseph W Adelsberger, Dawei Huang, Richard A. Lempicki, Xin Zheng, Qian Chen, Yanmei WangAbstract:The susceptibility of Macrophages to HIV-1 infection is modulated during monocyte Differentiation. IL-27 is an anti-HIV cytokine that also modulates monocyte activation. In this study, we present new evidence that IL-27 promotes monocyte Differentiation into Macrophages that are nonpermissive for HIV-1 infection. Although IL-27 treatment does not affect expression of Macrophage Differentiation markers or Macrophage biological functions, it confers HIV resistance by down-regulating spectrin β nonerythrocyte 1 (SPTBN1), a required host factor for HIV-1 infection. IL-27 down-regulates SPTBN1 through a TAK-1–mediated MAPK signaling pathway. Knockdown of SPTBN1 strongly inhibits HIV-1 infection of Macrophages; conversely, overexpression of SPTBN1 markedly increases HIV susceptibility of IL-27–treated Macrophages. Moreover, we demonstrate that SPTBN1 associates with HIV-1 gag proteins. Collectively, our results underscore the ability of IL-27 to protect Macrophages from HIV-1 infection by down-regulating SPTBN1, thus indicating that SPTBN1 is an important host target to reduce HIV-1 replication in one major element of the viral reservoir.
Kristy B Lidie - One of the best experts on this subject based on the ideXlab platform.
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il 27 inhibits hiv 1 infection in human Macrophages by down regulating host factor sptbn1 during monocyte to Macrophage Differentiation
Cytokine, 2013Co-Authors: Kristy B Lidie, Tauseef Rehman, Robert Laurie Dewar, Joseph W Adelsberger, Dawei Huang, Richard A. Lempicki, Xin Zheng, Qian Chen, Yanmei WangAbstract:Macrophages represent a major target and viral reservoir of HIV-1 infection. The susceptibility of Macrophages to HIV-1 infection is modulated during monocyte Differentiation. IL-27 is an antiviral cytokine which also plays a role in monocyte activation. Here, we present new evidence that IL-27 promotes monocyte Differentiation into Macrophages that are non-permissive for HIV-1 infection. While IL-27 treatment does not affect expression of Macrophage Differentiation markers or Macrophage biological functions, it confers HIV resistance by down-regulating SPTBN1, a required host factor for HIV-1 infection. IL-27 down-regulates SPTBN1 during monocyte Differentiation through a TAK-1-mediated MAPK signaling pathway. Knockdown of SPTBN1 strongly inhibits HIV-1 infection of Macrophages; conversely, overexpression of SPTBN1 markedly increases HIV susceptibility of IL-27 treated Macrophages. Moreover, we demonstrate that SPTBN1 associates with HIV-1 gag proteins. Collectively, our results underscore the ability of IL-27 to protect Macrophages from HIV-1 infection by down-regulating SPTBN1 during monocyte to Macrophage Differentiation without altering other Macrophage biological functions, thus indicating IL-27 as a potential immunotherapeutic reagent to prevent HIV-1 infection.
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il 27 inhibits hiv 1 infection in human Macrophages by down regulating host factor sptbn1 during monocyte to Macrophage Differentiation
Journal of Experimental Medicine, 2013Co-Authors: Kristy B Lidie, Tauseef Rehman, Robert Laurie Dewar, Joseph W Adelsberger, Dawei Huang, Richard A. Lempicki, Xin Zheng, Qian Chen, Yanmei WangAbstract:The susceptibility of Macrophages to HIV-1 infection is modulated during monocyte Differentiation. IL-27 is an anti-HIV cytokine that also modulates monocyte activation. In this study, we present new evidence that IL-27 promotes monocyte Differentiation into Macrophages that are nonpermissive for HIV-1 infection. Although IL-27 treatment does not affect expression of Macrophage Differentiation markers or Macrophage biological functions, it confers HIV resistance by down-regulating spectrin β nonerythrocyte 1 (SPTBN1), a required host factor for HIV-1 infection. IL-27 down-regulates SPTBN1 through a TAK-1–mediated MAPK signaling pathway. Knockdown of SPTBN1 strongly inhibits HIV-1 infection of Macrophages; conversely, overexpression of SPTBN1 markedly increases HIV susceptibility of IL-27–treated Macrophages. Moreover, we demonstrate that SPTBN1 associates with HIV-1 gag proteins. Collectively, our results underscore the ability of IL-27 to protect Macrophages from HIV-1 infection by down-regulating SPTBN1, thus indicating that SPTBN1 is an important host target to reduce HIV-1 replication in one major element of the viral reservoir.
Tomas Stopka - One of the best experts on this subject based on the ideXlab platform.
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epigenetic silencing of the oncogenic mir 17 92 cluster during pu 1 directed Macrophage Differentiation
The EMBO Journal, 2011Co-Authors: Vit Pospisil, Jiri Zavadil, Karin Vargova, Juraj Kokavec, Jana Rybarova, Filipp Savvulidi, E Necas, Peter Laslo, Anna Jonasova, Tomas StopkaAbstract:The oncogenic cluster miR-17-92 encodes seven related microRNAs that regulate cell proliferation, apoptosis and development. Expression of miR-17-92 cluster is decreased upon cell Differentiation. Here, we report a novel mechanism of the regulation of miR-17-92 cluster. Using transgenic PU.1−/− myeloid progenitors we show that upon Macrophage Differentiation, the transcription factor PU.1 induces the secondary determinant Egr2 which, in turn, directly represses miR-17-92 expression by recruiting histone demethylase Jarid1b leading to histone H3 lysine K4 demethylation within the CpG island at the miR-17-92 promoter. Conversely, Egr2 itself is targeted by miR-17-92, indicating existence of mutual regulatory relationship between miR-17-92 and Egr2. Furthermore, restoring EGR2 levels in primary acute myeloid leukaemia blasts expressing elevated levels of miR-17-92 and low levels of PU.1 and EGR2 leads to downregulation of miR-17-92 and restored expression of its targets p21CIP1 and BIM. We propose that upon Macrophage Differentiation PU.1 represses the miR-17-92 cluster promoter by an Egr-2/Jarid1b-mediated H3K4 demethylation mechanism whose deregulation may contribute to leukaemic states.
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the oncogenic mir 17 92 microrna cluster is inhibited by egr2 during Macrophage Differentiation via jarid1b mediated histone 3 lysine 4 demethylation
Blood, 2010Co-Authors: Vit Pospisil, Jiri Zavadil, Karin Vargova, Juraj Kokavec, Jana Rybarova, Filipp Savvulidi, E Necas, Peter Laslo, Tomas StopkaAbstract:Abstract 390 The miR-17-92 cluster (Oncomir1) encodes seven related microRNAs associated with cell proliferation, apoptosis and development and is overexpressed in number of malignancies including myeloid leukemias. The miR-17-92 cluster is highly expressed in myeloid progenitors, while it becomes downregulated upon the onset of Macrophage Differentiation. Conversely, sustained expression of miR-17-92 is associated with a Differentiation blockade (Fontana 2007). Here we report a novel mechanism of the regulation of miR-17-92 cluster within differentiating myeloid progenitors. During Macrophage Differentiation, the myeloid transcription factor PU.1 transcriptionally induces the secondary determinant Early growth factor 2 (Egr2). Subsequently, Egr2 binds to the miR-17-92 cluster promoter and recruits histone demethylase Jarid1b resulting in histone H3 lysine K4 (H3K4) demethylation within the CpG island upstream miR-17-92 cluster leading to the repression of miR-17-92 expression. Reporter assays using deletion constructs of the miR-17-92 promoter region revealed that Egr2 is required for targeting the Jarid1b onto critical minimal region within CpG island of upstream miR-17-92 locus and its decreased H3K4 methylation. In addition, functional assays identified the 3'UTR of Egr2 as the target of multiple miRNAs of the miR-17-92 cluster, indicating existence of a mutual regulation between miR-17-92 cluster and Egr2, putatively involved in Macrophage Differentiation characterized by a bistable state, where Egr2 negatively regulates miR-17-92 cluster in differentiating cells and, in turn, miR-17-92 cluster negatively regulates Egr2 in highly proliferating progenitor cells to achieve homeostatic regulation. Ectopic expression of miR-17-92 cluster within myeloid progenitors blocked Macrophage Differentiation indicating that leukemogenesis may involve miR-17-92 mediated Differentiation blockade. To determine if the newly identified negative regulatory mechanism of miR-17-92 is involved in leukemogenesis, we tested peripheral blood mononuclear cells isolated from acute myeloid leukemia (AML) patients (N=27). 14 of 27 AML patients exhibited significantly downregulated transcriptional factors PU.1 and Egr2 and high levels of the miR-17-92 cluster expression. Ectopic expression of Egr2 within AML blast cells (N=2) led to decreased levels of miR-17-92 and restored the expression of p21 and BIM, two established miR-17-92 targets downregulated in AML. We conclude that PU.1 represses miR-17-92 cluster during Macrophage Differentiation by Egr2 mediated recruitment of the Jarid1b demethylase and that dysregulation in the miR-17-92 repression mechanism may contribute to the pathogenesis of AML. (Grants # IGA 10310-3, MSMT 2B06077, 0021620806, LC06044, SVV-2010-254260507). Disclosures: No relevant conflicts of interest to declare.
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transcription factors pu 1 and egr2 inhibits the oncogenic microrna cluster mir 17 92 during Macrophage Differentiation
Blood, 2008Co-Authors: Vit Pospisil, Jiri Zavadil, Karin Vargova, Juraj Kokavec, E Necas, Pavel Burda, Tomas StopkaAbstract:PU.1 (Sfpi1) is an ets family transcription factor required for the proper generation of both myeloid and lymphoid lineages. Distinct nuclear levels of PU.1 are required for Macrophage Differentiation (DeKoter 2000). MicroRNAs are a novel class of 22nt long non-coding post-transcriptional regulators, associated with Differentiation, development and carcinogenesis. To identify miRNAs involved in PU.1 dependent hematopoietic Differentiation we used PU.1-null hematopoietic progenitor cells stably expressing PU.1 fused to the estrogen receptor ligand-binding domain inducible by tamoxifen (PUER) (Walsh 2002). PU.1 affected expression approximately 100 mature miRNA. Among them, we have observed that PU.1 downregulates members of miR-17~92 cluster and its paralog miR-106b~25 previously associated with Macrophage Differentiation, apoptosis and hematologic and other malignancies (Ota 2004, Hayashita 2005, Fontana 2008). During Macrophage Differentiation miR-17~92 becomes downregulated and its sustained expression is associated with the Differentiation block (Fontana 2007). In tamoxifen-stimulated PUER cells, PU.1 efficiently downregulates mature miRNAs of the miR-17~92 (-17.5p, -20a, -92) cluster and its paralog miR-106b~25 (but not miR-106a~363) within 96 hours and in dose dependent manner. PU.1 in the same cells activates expression of Egr2, myeloid transcription factor promoting Macrophage transcriptional program a putative 8-mer-seed sequence-containing target of miR-17~92 cluster (predicted by TargetScan). We tested whether PU.1 represses expression of miR-17~92 cluster by inducing Egr2. We demonstrate that ectopic expression of Egr2 in unstimulated PUER cells inhibited expression of miR-17~92 cluster, both at the levels of mature miRs and pri-miRNAs, and induced expression of Macrophage Differentiation markers (Cd14, Csf1r) coupled with cell cycle arrest. Trichostatin-dependent derepression of miR-17~92 indicated that its expression is regulated at the chromatin level. Chromatin immunoprecipitation revealed specific Egr2 occupancy within the regulatory region upstream of the miR-17~92 cluster. Our data indicate that in differentiating cells, a mechanism exists involving direct repression of the miR-17~92 cluster that in turn has the potential to inhibit Egr2 expression. We have tested this mechanisms in peripheral blood mononuclear cells isolated from acute myeloid leukemia (AML) patients (N=9) where levels of PU.1 and Egr2 are significantly lower that in normal controls. 5 out of 9 AML patients significantly overexpressed miR- 17.5p, miR-20a, miR-92 coinciding with downregulation of its established targets p21 and BIM. Rescue of Egr2 in AML cells (N=2) led to downregulation of miR-17~92 cluster and upregulation of BIM mRNA levels coincident with induction of apoptosis. We conclude that PU.1 regulates transcription of the miR-17~92 cluster by inducing Egr2 and demonstrate this mechanism in differentiating Macrophages and its disruption in AML cells.
Donald L. Durden - One of the best experts on this subject based on the ideXlab platform.
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rac2 controls tumor growth metastasis and m1 m2 Macrophage Differentiation in vivo
PLOS ONE, 2014Co-Authors: Shweta Joshi, Alok R. Singh, Muamera Zulcic, Donald L. Durden, Lei Bao, Karen Messer, Trey Ideker, Janusz DutkowskiAbstract:Although it is well-established that the Macrophage M1 to M2 transition plays a role in tumor progression, the molecular basis for this process remains incompletely understood. Herein, we demonstrate that the small GTPase, Rac2 controls Macrophage M1 to M2 Differentiation and the metastatic phenotype in vivo. Using a genetic approach, combined with syngeneic and orthotopic tumor models we demonstrate that Rac2-/- mice display a marked defect in tumor growth, angiogenesis and metastasis. Microarray, RT-PCR and metabolomic analysis on bone marrow derived Macrophages isolated from the Rac2-/- mice identify an important role for Rac2 in M2 Macrophage Differentiation. Furthermore, we define a novel molecular mechanism by which signals transmitted from the extracellular matrix via the α4β1 integrin and MCSF receptor lead to the activation of Rac2 and potentially regulate Macrophage M2 Differentiation. Collectively, our findings demonstrate a Macrophage autonomous process by which the Rac2 GTPase is activated downstream of the α4β1 integrin and the MCSF receptor to control tumor growth, metastasis and Macrophage Differentiation into the M2 phenotype. Finally, using gene expression and metabolomic data from our Rac2-/- model, and information related to M1-M2 Macrophage Differentiation curated from the literature we executed a systems biologic analysis of hierarchical protein-protein interaction networks in an effort to develop an iterative interactome map which will predict additional mechanisms by which Rac2 may coordinately control Macrophage M1 to M2 Differentiation and metastasis.
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abstract c61 a Macrophage autonomous α4β1integrin syk rac2 signaling axis controls Macrophage Differentiation tumor growth and metastasis
Cancer Research, 2013Co-Authors: Shweta Joshi, Muamera Zulcic, Karen Messer, Alok Singh, Bao Lei, Donald L. DurdenAbstract:Macrophages, a major leukocyte population present in tumors, play an essential role in promoting tumor growth by affecting angiogenesis, immune suppression, invasion and metastasis. Despite considerable research efforts, the signal transduction events within Macrophages which encode the complex cascade of events required for tumor growth and polarization of Macrophages are poorly understood. Our previous findings demonstrate that α4β1 and αvβ3 integrin directed cell migration on specific extracellular matrices (ECM) requires a specific kinase-GTPase pair, Syk-Rac2. This pathway was shown to regulate the ECM dependent postnatal angiogenic response with no defect in vascular development. Herein, we have linked this ECM dependent signaling pathway in Macrophages to the regulation of M2 Macrophage Differentiation and to the regulation of tumor growth, invasion and metastasis. Using mouse genetic models, we provide direct evidence that a Macrophage specific, α4β1 integrin dependent Syk-Rac2 signaling axis acts in concert with the p110γ isoform (PTEN-PI-3 kinase pathway) to control HIF1α levels, tumor growth and metastasis. We report a novel proteasome/E3 ligase dependent mechanism by which PI-3 kinase regulates HIF1α levels under hypoxic conditions in the stromal compartment. Moreover, treatment with Syk or PI-3 kinase inhibitors demonstrate potent activity in multiple metastatic models. The results define a novel molecular mechanism for the regulation of HIF1α and a Macrophage autonomous signaling pathway that is required for alterations in the ECM and the provisional integrin to regulate tumor metastasis and suggest treatment for metastatic disease targeting this pathway in the M2 Macrophage compartment. Citation Format: Shweta Joshi, Alok Ranjan Singh, Muamera Zulcic, Bao Lei, Karen Messer, Donald L. Durden. A Macrophage autonomous α4β1integrin-Syk-Rac2 signaling axis controls Macrophage Differentiation, tumor growth, and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C61.
Xin Zheng - One of the best experts on this subject based on the ideXlab platform.
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il 27 inhibits hiv 1 infection in human Macrophages by down regulating host factor sptbn1 during monocyte to Macrophage Differentiation
Cytokine, 2013Co-Authors: Kristy B Lidie, Tauseef Rehman, Robert Laurie Dewar, Joseph W Adelsberger, Dawei Huang, Richard A. Lempicki, Xin Zheng, Qian Chen, Yanmei WangAbstract:Macrophages represent a major target and viral reservoir of HIV-1 infection. The susceptibility of Macrophages to HIV-1 infection is modulated during monocyte Differentiation. IL-27 is an antiviral cytokine which also plays a role in monocyte activation. Here, we present new evidence that IL-27 promotes monocyte Differentiation into Macrophages that are non-permissive for HIV-1 infection. While IL-27 treatment does not affect expression of Macrophage Differentiation markers or Macrophage biological functions, it confers HIV resistance by down-regulating SPTBN1, a required host factor for HIV-1 infection. IL-27 down-regulates SPTBN1 during monocyte Differentiation through a TAK-1-mediated MAPK signaling pathway. Knockdown of SPTBN1 strongly inhibits HIV-1 infection of Macrophages; conversely, overexpression of SPTBN1 markedly increases HIV susceptibility of IL-27 treated Macrophages. Moreover, we demonstrate that SPTBN1 associates with HIV-1 gag proteins. Collectively, our results underscore the ability of IL-27 to protect Macrophages from HIV-1 infection by down-regulating SPTBN1 during monocyte to Macrophage Differentiation without altering other Macrophage biological functions, thus indicating IL-27 as a potential immunotherapeutic reagent to prevent HIV-1 infection.
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il 27 inhibits hiv 1 infection in human Macrophages by down regulating host factor sptbn1 during monocyte to Macrophage Differentiation
Journal of Experimental Medicine, 2013Co-Authors: Kristy B Lidie, Tauseef Rehman, Robert Laurie Dewar, Joseph W Adelsberger, Dawei Huang, Richard A. Lempicki, Xin Zheng, Qian Chen, Yanmei WangAbstract:The susceptibility of Macrophages to HIV-1 infection is modulated during monocyte Differentiation. IL-27 is an anti-HIV cytokine that also modulates monocyte activation. In this study, we present new evidence that IL-27 promotes monocyte Differentiation into Macrophages that are nonpermissive for HIV-1 infection. Although IL-27 treatment does not affect expression of Macrophage Differentiation markers or Macrophage biological functions, it confers HIV resistance by down-regulating spectrin β nonerythrocyte 1 (SPTBN1), a required host factor for HIV-1 infection. IL-27 down-regulates SPTBN1 through a TAK-1–mediated MAPK signaling pathway. Knockdown of SPTBN1 strongly inhibits HIV-1 infection of Macrophages; conversely, overexpression of SPTBN1 markedly increases HIV susceptibility of IL-27–treated Macrophages. Moreover, we demonstrate that SPTBN1 associates with HIV-1 gag proteins. Collectively, our results underscore the ability of IL-27 to protect Macrophages from HIV-1 infection by down-regulating SPTBN1, thus indicating that SPTBN1 is an important host target to reduce HIV-1 replication in one major element of the viral reservoir.
