C/EBPβ Blocks p65 Phosphorylation and Thereby NF-κB-Mediated Transcription in TNF-Tolerant Cells

Zwergal, Andreas; Quirling, Martina; Saugel, Bernd; Huth, Kathleen; Sydlik, Carmen; Poli, Valeria; Neumeier, D.; Ziegler‐Heitbrock, H. W. L.; Brand, Korbinian

doi:10.4049/jimmunol.177.1.665

Cited by 56 publications

(53 citation statements)

References 48 publications

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“…In contrast, when THP-1 cells were preincubated for 72 h with a low TNF dose, no inhibition of IkBa proteolysis and NF-kB DNA-binding activity was found (19). Under this condition the transcription factor C/EBPb interacts with NF-kB-p65 and inhibits its phosphorylation, thereby blocking the expression of NF-kB-dependent target genes, for example, IL-8 (3). A recent report demonstrates that TNF induces glycogen synthesis kinase-3 (GSK3)-mediated crosstolerance to endotoxin in macrophages (20).…”

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confidence: 91%

“…The rapid induction of cytokines such as TNF, chemokines, and other antimicrobial effector molecules is fundamental for orchestrating a coordinated immune response. TNF tolerance means that preexposure to TNF reduces sensitivity to subsequent stimulation with this cytokine (3). This form of refractoriness is involved in the modulation of TNF signaling and may represent a protective mechanism preventing the cell and organism from excessive and/ or prolonged cytokine stimulation (4).…”

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confidence: 99%

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Identification of Two Forms of TNF Tolerance in Human Monocytes: Differential Inhibition of NF-κB/AP-1– and PP1-Associated Signaling

Günther

Vogt

Hampel

et al. 2014

The Journal of Immunology

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The molecular basis of TNF tolerance is poorly understood. In human monocytes we detected two forms of TNF refractoriness, as follows: absolute tolerance was selective, dose dependently affecting a small group of powerful effector molecules; induction tolerance represented a more general phenomenon. Preincubation with a high TNF dose induces both absolute and induction tolerance, whereas low-dose preincubation predominantly mediates absolute tolerance. In cells preincubated with the high TNF dose, we observed blockade of IκBα phosphorylation/proteolysis and nuclear p65 translocation. More prominent in cells preincubated with the high dose, reduced basal IκBα levels were found, accompanied by increased IκBα degradation, suggesting an increased IκBα turnover. In addition, a nuclear elevation of p50 was detected in tolerant cells, which was more visible following high-dose preincubation. TNF-induced phosphorylation of p65-Ser536, p38, and c-jun was inhibited, and basal inhibitory p65-Ser468 phosphorylation was increased in tolerant cells. TNF tolerance induced by the low preincubation dose is mediated by glycogen synthesis kinase-3, whereas high-dose preincubation-mediated tolerance is regulated by A20/glycogen synthesis kinase-3 and protein phosphatase 1–dependent mechanisms. To our knowledge, we present the first genome-wide analysis of TNF tolerance in monocytic cells, which differentially inhibits NF-κB/AP-1–associated signaling and shifts the kinase/phosphatase balance. These forms of refractoriness may provide a cellular paradigm for resolution of inflammation and may be involved in immune paralysis.

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confidence: 91%

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confidence: 99%

Identification of Two Forms of TNF Tolerance in Human Monocytes: Differential Inhibition of NF-κB/AP-1– and PP1-Associated Signaling

Günther

Vogt

Hampel

et al. 2014

The Journal of Immunology

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“…Molecular mechanisms underlying this phenomenon are currently unclear, but like C/EBPb in macrophages, direct, physical interactions of C/EBPs with NF-kB subunits may be involved in their inhibitory actions. 26 In this report, we show both PPARg and C/EBPs control the fate of adipocytes by suppression of NF-kB. Currently, it is undetermined whether both factors regulate activity of NF-kB independently or cooperate in a single pathway.…”

Section: Selective Loss Of Adipocytes By Tnf-a M Tamai Et Almentioning

confidence: 93%

“…37 A previous report indicated that C/EBPb may inhibit activation of NF-kB in monocytic cells. 26 However, information is still limited regarding regulation of NF-kB by C/EBP members. In particular, regulation of NFkB by C/EBPs other than C/EBPb has not been elucidated.…”

Section: Selective Loss Of Adipocytes By Tnf-a M Tamai Et Almentioning

confidence: 99%

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Selective deletion of adipocytes, but not preadipocytes, by TNF-α through C/EBP- and PPARγ-mediated suppression of NF-κB

Tamai

Shimada

Hiramatsu

et al. 2010

Laboratory Investigation

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Tumor necrosis factor-a (TNF-a) is a key regulator of adipose tissue mass, but mechanisms underlying this effect have not been fully elucidated. We found that exposure to TNF-a caused a significant decrease in the number of adipocytes, but not preadipocytes. Subsequent experiments revealed that TNF-a selectively deleted adipocytes through induction of apoptosis. Following exposure to TNF-a, rapid activation of nuclear factor-kB (NF-kB) was observed only in preadipocytes, but not in adipocytes. Inhibition of NF-kB rendered preadipocytes susceptible to TNF-a-induced apoptosis, suggesting that different activity of NF-kB is the determinant for the distinct apoptotic responses. During adipocyte differentiation, expression and activity of peroxisome proliferator-activated receptor-g (PPARg) were upregulated. Treatment of preadipocytes with a PPARg agonist attenuated NF-kB activation and rendered the cells vulnerable to TNF-a-induced apoptosis. Conversely, treatment of adipocytes with a PPARg antagonist enhanced NF-kB activation and conferred resistance to TNF-a-induced apoptosis, suggesting involvement of PPARg in the suppression of NF-kB in adipocytes. We also found that, following differentiation, expression and activity of CCAAT/ enhancer binding protein (C/EBP), especially C/EBPa and C/EBPb, were upregulated in adipocytes. Overexpression of individual C/EBPs significantly inhibited activation of NF-kB in preadipocytes. Furthermore, transfection with siRNA for C/EBPa or C/EBPb enhanced activity of NF-kB in adipocytes, suggesting that C/EBP is also involved in the repression of NF-kB in adipocytes. These results suggested novel mechanisms by which TNF-a selectively deletes adipocytes in the adipose tissue. The C/EBP-and PPARg-mediated suppression of NF-kB may contribute to TNF-a-related loss of adipose tissue mass under certain pathological situations, such as cachexia.

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Ubiquitination, phosphorylation, and acetylation—triple threat in muscle wasting

Hasselgren

2007

Journal Cellular Physiology

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Loss of muscle mass is commonly seen in patients with critical illness and is associated with increased expression of multiple genes controlling protein breakdown. Transcription factors that are activated during muscle wasting include NF-kB and members of the FOXO and C/EBP transcription factor families. The activity of these transcription factors is regulated by multiple posttranslational modifications, including ubiquitination, phosphorylation, and acetylation, providing for a complex and integrated network of regulatory mechanisms in muscle wasting. Targeting posttranslational modifications of transcription factors may prove important in the prevention and treatment of the debilitating consequences of muscle wasting.

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C/EBPβ Blocks p65 Phosphorylation and Thereby NF-κB-Mediated Transcription in TNF-Tolerant Cells

Cited by 56 publications

References 48 publications

Identification of Two Forms of TNF Tolerance in Human Monocytes: Differential Inhibition of NF-κB/AP-1– and PP1-Associated Signaling

Identification of Two Forms of TNF Tolerance in Human Monocytes: Differential Inhibition of NF-κB/AP-1– and PP1-Associated Signaling

Selective deletion of adipocytes, but not preadipocytes, by TNF-α through C/EBP- and PPARγ-mediated suppression of NF-κB

Ubiquitination, phosphorylation, and acetylation—triple threat in muscle wasting

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