Cooperative interaction of C/EBPβ and Tat modulates MCP-1 gene transcription in astrocytes

Abraham, Selvajothi; Sweet, Thersa; Sawaya, Bassel E.; Rappaport, Jay; Khalili, Kamel; Amini, Shohreh

doi:10.1016/j.jneuroim.2004.11.009

Cited by 51 publications

(40 citation statements)

References 59 publications

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“…These signaling cascades are believed to be activated following interaction of Tat with various cell surface receptors including integrin receptors, members of the vascular endothelial growth factor receptor family (45,46), the ␤-chemokine receptors (CCR2 and CXCR4 (47,48)), as well as with integrins ␣ 5 ␤ 1 and ␣ v ␤ 3 (49,50). Extracellular Tat translocates to the nucleus where it is known to activate various transcription factors including AP-1, Sp-1, CREB, and NF-B (36,41,43,(51)(52)(53).…”

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confidence: 99%

IL-10 Regulation by HIV-Tat in Primary Human Monocytic Cells: Involvement of Calmodulin/Calmodulin-Dependent Protein Kinase-Activated p38 MAPK and Sp-1 and CREB-1 Transcription Factors

Gee

Angel

Mishra

et al. 2007

The Journal of Immunology

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The anti-inflammatory cytokine, IL-10 plays an important role in HIV immunopathogenesis. The HIV accessory protein, Tat is not only critical for viral replication, but affects the host immune system by influencing cytokine production including IL-10. During HIV infection, IL-10 production by monocytic cells is up-regulated, representing a critical pathway by which HIV may induce immunodeficiency. Herein, we show that extracellular Tat-induced IL-10 expression in normal human monocytes. To understand the signaling pathways underlying HIV-Tat induced IL-10 transcription, we investigated the involvement of MAPK as well as calcium signaling and the downstream transcription factor(s). Our results suggest that Tat-induced calcium influx regulated IL-10 transcription in monocytic cells. The experiments designed to further understand the molecules involved in the calcium signaling suggested that calmodulin and calmodulin-dependent protein kinase-II (CaMK-II)-activated p38 MAPK played a role in extracellular Tat-induced IL-10 expression in primary human monocytes. Furthermore, Tat-induced IL-10 expression was regulated by p38 MAPK- and CaMK II-activated CREB-1 as well as Sp-1 transcription factors. Taken together, our results suggest that extracellular HIV-Tat induced IL-10 transcription in primary human monocytes is regulated by CREB-1 and Sp-1 transcription factors through the activation of calmodulin/CaMK-II-dependent p38 MAPK.

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confidence: 99%

IL-10 Regulation by HIV-Tat in Primary Human Monocytic Cells: Involvement of Calmodulin/Calmodulin-Dependent Protein Kinase-Activated p38 MAPK and Sp-1 and CREB-1 Transcription Factors

Gee

Angel

Mishra

et al. 2007

The Journal of Immunology

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“…It is tempting to speculate that the DS1 site may be involved in mediating Tat transactivation and productive virus replication perhaps by tethering and stabilizing Tat binding to the TAR element. Tat has been shown to increase expression of the C/EBP␤ protein and binding of C/EBP␤ to DNA in vitro (55), in addition to physically and functionally interacting (in vitro and in vivo) with C/EBP␤ to induce interleukin 6 and MCP-1 (monocyte chemoattractant protein 1 or CCL2 (55)(56)(57)(58)). Moreover, Mameli et al (58) demonstrated that the Tat-C/EBP␤ functional and physical association is mediated through cyclin T1/cdk9 in U-87MG astrocytic cells and possibly influences cates in perivascular macrophages, and spreads to resident macrophages (1,2,8,69).…”

Section: Discussionmentioning

confidence: 99%

Regulation of SIVmac239 Basal Long Terminal Repeat Activity and Viral Replication in Macrophages

Ravimohan

Gama

Barber

et al. 2010

Journal of Biological Chemistry

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CCAAT/enhancer-binding protein (C/EBP) ␤ and C/EBP sites in the HIV-1 long terminal repeat (LTR) are crucial for HIV-1 replication in monocyte/macrophages and for the ability of interferon ␤ (IFN␤) to inhibit ongoing active HIV replication in these cells. This IFN␤-mediated down-regulation involves induction of the truncated, dominant-negative isoform of C/EBP␤ referred to as liver-enriched transcriptional inhibitory protein (LIP). Although binding of the C/EBP␤ isoform to C/EBP sites in the simian immunodeficiency virus (SIV) LTR has previously been examined, the importance of these sites in core promoter-mediated transcription, virus replication, IFN␤-mediated regulation, and the relative binding of the two isoforms (C/EBP␤ and LIP) has not been investigated. Here, we specifically examine two C/EBP sites, JC1 (؊100 bp) and DS1 (؉134 bp), located within the minimal region of the SIV LTR, required for core promoter-mediated transcription and virus replication in macrophages. Our studies revealed that the JC1 but not DS1 C/EBP site is important for basal level transcription, whereas the DS1 C/EBP site is imperative for productive virus replication in primary macrophages. In contrast, either JC1 or DS1 C/EBP site is sufficient to mediate IFN␤-induced down-regulation of SIV LTR activity and virus replication in these cells. We also characterized the differential binding properties of C/EBP␤ and LIP to the JC1 and DS1 sites. In conjunction with previous studies from our laboratory, we demonstrate the importance of these sites in virus gene expression, and we propose a model for their role in establishing latency and persistence in macrophages in the brain.

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“…However, detection of extracellular Tat as well as Nef in the brain has not been confirmed. Recently, intracellular Tat has been shown to stimulate the CCL2/MCP-1 promoter in human astrocytic cells (Abraham et al, 2003;Abraham et al, 2005). By contrast, in monocytes, Tat has been shown to be dispensable for HIV-mediated induction of CCL2/MCP-1 expression (Mengozzi et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Nef upregulates CCL2/MCP-1 expression in astrocytes in a myristoylation- and calmodulin-dependent manner

Lehmann

Masanetz

Krämer

et al. 2006

Journal of Cell Science

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27 kDa accessory HIV and simian immunodeficiency virus (SIV) protein necessary for efficient virus replication and high viral load, has for several years been considered as a progression factor to AIDS (Greene and Peterlin, 2002). According to several excellent reviews, a variety of diverse functions including downregulation of cell-surface molecules have been assigned to the protein (Das and Jameel, 2005;Piguet and Trono, 1999;Roeth and Collins, 2006). Moreover, HIV-associated dementia (HAD) correlates with infiltration of monocytes into the brain. The accessory HIV-1 negative factor (Nef) protein, which modulates several signaling pathways, is constitutively present in persistently infected astroctyes. We demonstrated that monocytes responded with chemotaxis when subjected to cell culture supernatants of nef-expressing astrocytic U251MG cells. Using a protein array, we identified CC chemokine ligand 2/monocyte chemotactic protein-1 (CCL2/MCP-1) as a potential chemotactic factor mediating this phenomenon. CCL2/MCP-1 upregulation by Nef was further confirmed by ribonuclease protection assay, RT-PCR and ELISA. By applying neutralizing antibodies against CCL2/MCP-1 and using CCR2-deficient monocytes, we confirmed CCL2/MCP-1 as the exclusive factor secreted by nefexpressing astrocytes capable of attracting monocytes. Additionally, we showed that Nef-induced CCL2/MCP-1 expression depends on the myristoylation moiety of Nef and requires functional calmodulin. In summary, we suggest that Nef-induced CCL2/MCP-1 expression in astrocytes contributes to infiltration of monocytes into the brain, and thereby to progression of HAD.

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Cooperative interaction of C/EBPβ and Tat modulates MCP-1 gene transcription in astrocytes

Cited by 51 publications

References 59 publications

IL-10 Regulation by HIV-Tat in Primary Human Monocytic Cells: Involvement of Calmodulin/Calmodulin-Dependent Protein Kinase-Activated p38 MAPK and Sp-1 and CREB-1 Transcription Factors

IL-10 Regulation by HIV-Tat in Primary Human Monocytic Cells: Involvement of Calmodulin/Calmodulin-Dependent Protein Kinase-Activated p38 MAPK and Sp-1 and CREB-1 Transcription Factors

Regulation of SIVmac239 Basal Long Terminal Repeat Activity and Viral Replication in Macrophages

HIV-1 Nef upregulates CCL2/MCP-1 expression in astrocytes in a myristoylation- and calmodulin-dependent manner

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