Cooperation of NFκB and CREB to induce synergistic IL-6 expression in astrocytes

Spooren, Anneleen; Kooijman, Ron; Lintermans, Béatrice; Craenenbroeck, Kathleen Van; Vermeulen, Linda; Haegeman, Guy; Gerlo, Sarah

doi:10.1016/j.cellsig.2010.01.018

Cited by 63 publications

(76 citation statements)

References 54 publications

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“…We have shown before that combined β-adrenergic and TNF receptor triggering elicits synergistic IL-6 expression in human astrocytoma 1321N1 cells at protein, mRNA and promoter level [29]. Here we show that addition of the pro-inflammatory cytokine IL-1β to the isoproterenol and TNF-α treatment protocol substantially strengthened this synergistic IL-6 production, inducing a "super"-synergy.…”

Section: Il-1β Potently Enhances the Isoproterenol/tnf-α-induced Il-6supporting

confidence: 48%

“…The MAP kinases p38, JNK and ERK1/2, previously shown to be potently activated by TNF-α in 1321N1 cells [29], were also activated by IL-1β (Fig. 2a, b, c and f).…”

Section: Il-1β Does Not Enhance Isoproterenol/tnf-α-induced Il-6 Prommentioning

confidence: 61%

“…However, triple induction did not lead to synergistic activation of any of the MAP kinases compared to double induction. Additionally, combined isoproterenol and TNF-α treatment activated CREB [29], and IL-1β also induced minor CREB phosphorylation, but M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 12 again triple induction did not induce synergistic CREB activation as compared to double induction ( Fig. 2d and f).…”

Section: Il-1β Does Not Enhance Isoproterenol/tnf-α-induced Il-6 Prommentioning

confidence: 99%

“…The 1321N1 cells used in this study were originally isolated from primary cultures of a cerebral glioma multiforme [27], and are often used as an astrocyte model [28]. We have shown before that combined β-adrenergic and TNF-receptor triggering induces synergistic IL-6 expression in 1321N1 cells via a transcriptional enhancer mechanism, involving the cooperative recruitment of CREB, NF-θB and CBP to the IL-6 promoter [29]. Here, we describe that IL-1β can further enhance IL-6 production via a post-transcriptional mechanism involving mRNA stabilization.…”

Section: Page 4 Of 48mentioning

confidence: 99%

“…2). Furthermore, we analyzed the degradation rates of two other genes that are induced by isoproterenol, TNF-α and IL-1β in 1321N1 cells, namely COX-2 and IL-8 [29,38]. COX-2 showed a synergistic mRNA induction and an mRNA degradation pattern that was very comparable to the one observed for IL-6 ( As the 3"UTR is the main target for mRNA-(de)stabilizing mechanisms, we also studied IL-6 mRNA stability using a reporter gene assay.…”

Section: Page 13 Of 48mentioning

confidence: 99%

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IL-1β potently stabilizes IL-6 mRNA in human astrocytes

Spooren

Mestdagh

Rondou

et al. 2011

Biochemical Pharmacology

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Uncontrolled expression of IL-6 in the central nervous system is associated with neurodegenerative pathology and glioma development. Astrocytes are the predominant source of IL-6 in the central nervous system, and they are characteristically susceptible to synergistic IL-6 expression. Combined β-adrenergic and TNF-receptor triggering induces synergistic IL-6 expression in 1321N1 cells via a transcriptional enhancer mechanism. Here, we have investigated the molecular basis of the very potent "super"-synergistic IL-6 expression that is apparent after combined treatment of astrocytes with a β-adrenergic agonist, isoproterenol, and the inflammatory cytokines TNF-α and IL-1β. We found that IL-1β treatment strengthens the IL-6 synergy by inducing a distinct stabilization of IL-6 mRNA. Surprisingly, the mRNAstabilizing effect seems to be dependent on protein kinase C (PKC), but not on the prototypical mRNA-stabilizing kinase p38. Moreover, although the mRNA-binding protein HuR basally stabilizes IL-6 mRNA, the mRNA-stabilizing effect of IL-1β is independent of HuR. Our data using pharmacological inhibitors suggest PKC is an important modulator of IL-6 expression in the central nervous system and this might have therapeutic implications.

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Section: Il-1β Potently Enhances the Isoproterenol/tnf-α-induced Il-6supporting

confidence: 48%

“…The MAP kinases p38, JNK and ERK1/2, previously shown to be potently activated by TNF-α in 1321N1 cells [29], were also activated by IL-1β (Fig. 2a, b, c and f).…”

Section: Il-1β Does Not Enhance Isoproterenol/tnf-α-induced Il-6 Prommentioning

confidence: 61%

Section: Il-1β Does Not Enhance Isoproterenol/tnf-α-induced Il-6 Prommentioning

confidence: 99%

Section: Page 4 Of 48mentioning

confidence: 99%

Section: Page 13 Of 48mentioning

confidence: 99%

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IL-1β potently stabilizes IL-6 mRNA in human astrocytes

Spooren

Mestdagh

Rondou

et al. 2011

Biochemical Pharmacology

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NF‐κB, CRE and YY1 elements are key functional regulators of CMV promoter‐driven transient gene expression in CHO cells

Brown

Sweeney

Mainwaring

et al. 2015

Biotechnology Journal

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Transient gene expression (TGE) in CHO cells is utilized to produce material for use in early stage drug development. These systems typically utilize the cytomegalovirus (CMV) promoter to drive recombinant gene transcription. In this study, we have mechanistically dissected CMV-mediated TGE in CHO cells in order to identify the key regulators of this process. An in silico analysis of the promoter composition of transcription factor regulatory elements (TFREs) and the CHO cell repertoire of transcription factors identified eight TFREs as likely effectors of CMV activity. We determined the regulatory function of these elements by preventing their cognate transcription factors from binding at the CMV promoter. This was achieved by both scrambling promoter binding site sequences and using decoy molecules to sequester intracellular transcription factors. We determined that the vast majority of CMV activity is mediated by just two discrete TFREs, showing that simultaneous inhibition of NF-κB and CRE-mediated transactivation reduced CMV-driven transient secreted alkaline phosphatase (SEAP) production by over 75%. Further, we identified a mechanism by which CMV-mediated TGE is negatively regulated in CHO cells, showing that inhibition of YY1-mediated transrepression increased SEAP production 1.5-fold. This work enables optimization and control of CMV-mediated TGE in CHO cells, in order to improve transient protein production yields.

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Regulatory mechanisms underlying interleukin‐6 expression in murine brown adipocytes

Fu,

Murakami,

Hashimoto

et al. 2024

Cell Biochemistry & Function

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Three types of adipocytes, white, brown, and beige, regulate the systemic energy balance through the storage and expenditure of chemical energy. In addition, adipocytes produce various bioactive molecules known as adipokines. In contrast to white adipocyte‐derived molecules, less information is available on the adipokines produced by brown adipocytes (batokine). This study explored the regulatory expression of interleukin (IL)‐6 in cell culture studies. Norepinephrine or a nonselective β‐adrenergic receptor agonist increased the expression of IL‐6 in primary brown adipocytes and HB2 brown adipocytes. Treatment with forskolin (Fsk), an activator of the cAMP‐dependent protein kinase (PKA) pathway (downstream signaling of the β‐adrenergic receptor), efficiently stimulated IL‐6 expression in brown adipocytes and myotubes. Phosphorylated CREB and phosphorylated p38 MAP kinase levels were increased in Fsk‐treated brown adipocytes within 5 min. In contrast, a long‐term (∼60 min and ∼4 h) treatment with Fsk was required for increase in STAT3 phosphorylation and C/EBPβ expression, respectively. The PKA, p38 MAP kinase, STAT3, and C/EBPβ pathways are required for the maximal IL‐6 expression induced by Fsk, which were verified by use of various inhibitors of these signal pathways. Vitamin C enhanced Fsk‐induced IL‐6 expression through the extracellular signal‐regulated kinase activity. The present study provides basic information on the regulatory expression of IL‐6 in activated brown adipocytes.

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Cooperation of NFκB and CREB to induce synergistic IL-6 expression in astrocytes

Cited by 63 publications

References 54 publications

IL-1β potently stabilizes IL-6 mRNA in human astrocytes

IL-1β potently stabilizes IL-6 mRNA in human astrocytes

NF‐κB, CRE and YY1 elements are key functional regulators of CMV promoter‐driven transient gene expression in CHO cells

Regulatory mechanisms underlying interleukin‐6 expression in murine brown adipocytes

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