CCAAT/enhancer binding protein δ regulates glial proinflammatory gene expression

Valente, Tony; Straccia, Marco; Gresa-Arribas, Núria; Dentesano, Guido; Tusell, Josep Maria; Serratosa, Joan; Mancera, Pilar; Solà, Carme; Saura, Josep

doi:10.1016/j.neurobiolaging.2013.02.007

Cited by 29 publications

(35 citation statements)

References 57 publications

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“…The gene with the second highest upregulation, CEBPD , is a transcription factor that modulates many biological processes, including cell differentiation, motility, growth arrest, proliferation, and cell death. Though it was reported that CEBPD was induced by IFN-γ in certain cancers [24, 46], CEBPD functions both as a tumor suppressor and a tumor promoter [47]. Here we showed the predicted pathway of PD-L1 expression induced by IFN-γ, deduced from the results of microarray analysis.…”

Section: Discussionmentioning

confidence: 74%

“…The highest upregulation was seen in gene TP53INP2 (tumor protein p53 inducible nuclear protein 2), which regulates transcription and enhances starvation-induced autophagy [22]. The second highest upregulation was seen in gene CEBPD (CCAAT/enhancer binding protein [C/EBP] δ), which regulates proinflammatory gene expression [23, 24]. IFN-γ treatment downregulated some genes in UM-Chor1 cells > 1.5-fold relative to untreated controls ( P < 0.05; (Supplemental Figure 1B).…”

Section: Resultsmentioning

confidence: 99%

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Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab

et al. 2016

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Chordoma, a rare bone tumor derived from the notochord, has been shown to be resistant to conventional therapies. Checkpoint inhibition has shown great promise in immune-mediated therapy of diverse cancers. The anti-PD-L1 mAb avelumab is unique among checkpoint inhibitors in that it is a fully human IgG1 capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC) of PD-L1-expressing tumor cells. Here, we investigated avelumab as a potential therapy for chordoma. We examined 4 chordoma cell lines, first for expression of PD-L1, and in vitro for ADCC killing using NK cells and avelumab. PD-L1 expression was markedly upregulated by IFN-γ in all 4 chordoma cell lines, which significantly increased sensitivity to ADCC. Brachyury is a transcription factor that is uniformly expressed in chordoma. Clinical trials are ongoing in which chordoma patients are treated with brachyury-specific vaccines. Co-incubating chordoma cells with brachyury-specific CD8+ T cells resulted in significant upregulation of PD-L1 on the tumor cells, mediated by the CD8+ T cells' IFN-γ production, and increased sensitivity of chordoma cells to avelumab-mediated ADCC. Residential cancer stem cell subpopulations of chordoma cells were also killed by avelumab-mediated ADCC to the same degree as non-cancer stem cell populations. These findings suggest that as a monotherapy for chordoma, avelumab may enable endogenous NK cells, while in combination with T-cell immunotherapy, such as a vaccine, avelumab may enhance NK-cell killing of chordoma cells via ADCC.

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Section: Discussionmentioning

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab

et al. 2016

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“…Similarly, our previous study shows that 95 % of C/EBPδ signal is co-localized with GFAP-positive cells in App Tg mice [26]. Moreover, C/EBPδ is expressed in both astrocytes and microglia in the brain of mice treated with lipopolysaccharide (LPS) [33]. Although the possible involvement of non-astroglial cells in the expression of C/EBPδ cannot be entirely excluded, astrocytic C/EBPδ appears to play a major role in glial scar formation during wound healing because C/EBPδ is expressed mostly by reactive astrocytes after SCI.…”

Section: Discussionmentioning

confidence: 76%

Astrocytic CCAAT/Enhancer-Binding Protein Delta Contributes to Glial Scar Formation and Impairs Functional Recovery After Spinal Cord Injury

Wang

Hsu

et al. 2015

Mol Neurobiol

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After spinal cord injury, inflammatory reaction induces the aggregation of astrocytes to form a glial scar that eventually blocks axonal regeneration. Transcription factor CCAAT/enhancer-binding protein delta (C/EBPδ) is a regulatory protein of genes responsive to inflammatory factors, but its role in glial scar formation after spinal cord injury remains unknown. By using a model of moderate spinal cord contusion injury at the mid-thoracic level, we found that C/EBPδ was expressed mostly in the reactive astrocytes bordering the lesion in wild-type mice from 7 days after the injury. C/EBPδ-deficient mice showed reduced glial scar formation, more residual white matter, and better motor function recovery compared with wild-type mice 28 days after the injury. Upon interleukin (IL)-1β stimulation in vitro, the increased expression of C/EBPδ in reactive astrocytes inhibited RhoA expression and, subsequently, the ability of astrocyte migration. However, these reactive astrocytes also produced an increased amount of matrix metalloproteinase-3, which promoted the migration of non-IL-1β-treated, inactive astrocytes. Although the involvement of other non-astroglial C/EBPδ cannot be entirely excluded, our studies suggest that astrocytic C/EBPδ is integral to the inflammatory cascades leading to glial scar formation after spinal cord injury.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-015-9486-6) contains supplementary material, which is available to authorized users.

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“…This upregulation is rapid (3-4 h), transient, occurs concomitantly in many peripheral tissues and is not observed for C/EBPα (Alam et al 1992;Saito et al 1999). Gel shift and western blot studies have revealed that these increases also occur at the protein level (Damm et al 2011;Ejarque-Ortiz et al 2007a;Saito et al 1999;Valente et al 2013). Systemic inflammation induces a rapid increase of C/EBPβ immunoreactivity throughout the rat brain, being particularly strong in circumventricular organs, meninges and around blood vessels.…”

Section: Neuroinflammation By Systemic Lps Infusionmentioning

confidence: 99%

C/EBPβ and C/EBPδ transcription factors: Basic biology and roles in the CNS

Pulido-Salgado

Vidal-Taboada

Saura

2015

Progress in Neurobiology

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141

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CCAAT/enhancer binding protein δ regulates glial proinflammatory gene expression

Cited by 29 publications

References 57 publications

Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab

Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab

Astrocytic CCAAT/Enhancer-Binding Protein Delta Contributes to Glial Scar Formation and Impairs Functional Recovery After Spinal Cord Injury

C/EBPβ and C/EBPδ transcription factors: Basic biology and roles in the CNS

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