Induction of RelB Participates in Endotoxin Tolerance

Yoza, Barbara K.; Hu, Jean; Cousart, Sue L.; Forrest, Lolita M.; McCall, Charles E.

doi:10.4049/jimmunol.177.6.4080

Cited by 101 publications

(124 citation statements)

References 59 publications

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“…In this model, levels of p65 and p50 were not changed by endotoxin tolerance. Overexpression of RelB in THP-1 cells mimics the phenotype of endotoxin tolerance and vice versa, inhibition of RelB abolished the induction of tolerance (21). We observed a moderate ϳ2-fold increase in general DNA binding of p65 and p50 under conditions of endotoxin tolerance and, in agreement with the findings of Yoza et al (21), a highly significant 4-fold induction of p52 DNA binding.…”

Section: Discussionsupporting

confidence: 81%

“…Overexpression of RelB in THP-1 cells mimics the phenotype of endotoxin tolerance and vice versa, inhibition of RelB abolished the induction of tolerance (21). We observed a moderate ϳ2-fold increase in general DNA binding of p65 and p50 under conditions of endotoxin tolerance and, in agreement with the findings of Yoza et al (21), a highly significant 4-fold induction of p52 DNA binding. In endotoxin-tolerant THP-1 cells, RelB was found to associate with p65, resulting in a repression of the IL-1␤ promoter activity (21,34).…”

Section: Discussionsupporting

confidence: 81%

“…We observed a moderate ϳ2-fold increase in general DNA binding of p65 and p50 under conditions of endotoxin tolerance and, in agreement with the findings of Yoza et al (21), a highly significant 4-fold induction of p52 DNA binding. In endotoxin-tolerant THP-1 cells, RelB was found to associate with p65, resulting in a repression of the IL-1␤ promoter activity (21,34). To test whether p52 is also involved in the reduced expression of HIF-1␣ seen in tolerant cells, we knocked down p52 by a siRNA approach targeting the p52 precursor RelB/p100.…”

Section: Discussionsupporting

confidence: 80%

“…The human monocytic cell line THP-1 is a well-established model for studying the induction of endotoxin tolerance in monocytic cells (21). Endotoxin tolerance has been described in bacterial LPS-pretreated macrophages as the impaired release of proinflammatory cytokines on a subsequent challenge with LPS (22).…”

Section: Discussionmentioning

confidence: 99%

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Hypoxia-Inducible Factor (HIF) 1α Accumulation and HIF Target Gene Expression Are Impaired after Induction of Endotoxin Tolerance

Frede

Stockmann²,

Winning³

et al. 2009

The Journal of Immunology

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The oxygen-sensitive transcription factor hypoxia-inducible factor 1 (HIF-1) is known as the key regulator of hypoxia-induced gene expression. In addition to hypoxia, endotoxins such as bacterial LPS as well as proinflammatory cytokines have been shown to induce HIF-1, suggesting an integrative role for HIF-1 in conditions of hypoxia and inflammation. Cells can become tolerant to endotoxins by repetitive exposure to LPS. Herein, we studied the effect of endotoxin tolerance on HIF-1α accumulation and expression of HIF target genes in human monocytic cells and primary mouse peritoneal macrophages. Tolerant cells had reduced levels of HIF-1α under hypoxia, which was due to lowered levels of HIF-1α mRNA. HIF-1α expression is under control of NF-κB and increased DNA binding of the p52 subunit of NF-κB was found in tolerant cells. Knock down of p52 abolished the effects of endotoxin tolerance on HIF-1α expression, which suggest a negative regulatory role of p52 on HIF-1α transcription during endotoxin tolerance. Endotoxin tolerant cells showed diminished expression of the HIF target genes phosphoglycerate kinase 1 and adrenomedullin and reduced viability under hypoxic conditions, as well as a significantly reduced invasion. Peritoneal macrophages from endotoxin-tolerant mice made showed significantly reduced HIF-1α protein accumulation and subsequent HIF target gene expression. We conclude that endotoxin tolerance impairs HIF-1α induction which reduces the ability of monocytic cells to survive and function under hypoxic conditions.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Hypoxia-Inducible Factor (HIF) 1α Accumulation and HIF Target Gene Expression Are Impaired after Induction of Endotoxin Tolerance

Frede

Stockmann²,

Winning³

et al. 2009

The Journal of Immunology

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“…Our previous studies showed that RelB knockdown induced p65 binding to the proximal promoters of TNF␣ and IL-1␤ and, consequently, reactivated their transcription (27,42). To assess whether nucleosome repositioning to the permissive locations seen in T0 and T1 cells after RelB knockdown was associated with the induction of p65 binding, we measured p65 binding to the proximal NF-B (K3) site, which we previously showed is required for the transcription activation (27).…”

Section: Baf Chromatin-remodeling Complex Is Required For Nucleosome mentioning

confidence: 99%

Dynamic and Selective Nucleosome Repositioning during Endotoxin Tolerance

Gazzar

Liu

Yoza

et al. 2010

Journal of Biological Chemistry

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Sepsis is encoded by a sequel of transcription activation and repression events that initiate, sustain, and resolve severe systemic inflammation. The repression/silencing phase occurs in blood leukocytes of animals and humans following the initiation of systemic inflammation due to developing endotoxin tolerance. We previously reported that NF-B transcription factor RelB and histone H3 lysine methyltransferase G9a directly interact to induce facultative heterochromatin assembly and regulate epigenetic silencing during endotoxin tolerance, which is a major feature of sepsis. The general objective of this study was to assess whether dynamic temporal, structural, and positional changes of nucleosomes influence the sepsis phenotype. We used the THP-1 sepsis cell model to isolate mononucleosomes by rapid cell permeabilization and digestion of chromatin with micrococcal nuclease and then compared tumor necrosis factor ␣ (TNF␣) proximal promoter nucleosome alignment in endotoxin-responsive and -tolerant phenotypes. We found differential and dynamic repositioning of nucleosomes from permissive to repressive locations during the activation and silencing phases of transcription reprogramming and identified the following mechanisms that may participate in the process. 1) Two proximal nucleosomes repositioned to expose the primary NF-B DNA binding site in endotoxin-responsive cells, and this "promoter opening" required the ATP-independent chaperone NAP1 to replace the core histone H2A with the H2A.Z variant. 2) During RelB-dependent endotoxin tolerance, the two nucleosomes repositioned and masked the primary NF-B DNA binding site. 3) Small interfering RNA-mediated inhibition of RelB expression prevented repressive nucleosome repositioning and tolerance induction, but the "open" promoter required endotoxin-induced NF-B p65 promoter binding to initiate transcription, supporting the known requirement of p65 posttranslational modifications for transactivation. 4) Sustaining the permissive promoter state after RelB knockdown required ATP-dependent nucleosome remodeler BAF complex. Moreover, we found that forced expression of RelB in responsive cells induced repressive nucleosome positioning and silenced TNF␣ transcription, demonstrating the plasticity of nucleosome remodeling and its dependence on RelB. Our data suggest that nucleosome repositioning controls both the induction and epigenetic silencing phases of TNF␣ transcription associated with sepsis.

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The anti‐TLR4 monoclonal antibody Sa15‐21 enhances inflammatory cytokine production in LPS‐stimulated macrophages

et al. 2023

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Sa15-21, a monoclonal antibody against mouse Toll-like receptor (TLR) 4, can protect mice from lipopolysaccharide (LPS)/D-galactosamine-induced acute lethal hepatitis. Herein, we investigated the molecular mechanisms underlying Sa15-21-mediated regulation of TLR4 signaling in macrophages. Results showed that Sa15-21 enhanced the production of proinflammatory cytokines and attenuated the production of anti-inflammatory cytokines in LPS-stimulated macrophages. Western blotting analysis revealed that Sa15-21 pretreatment had no effect on NF-jB and MAPK signaling in LPSstimulated macrophages; however, Sa15-21 treatment alone led to a weak and delayed activation of NF-jB and MAPK signaling without any effect on proinflammatory cytokine production. By contrast, Sa15-21 failed to induce the activation of interferon regulatory factor 3. Taken together, our results indicate that Sa15-21 sensitizes macrophages to facilitate the inflammatory response via TLR signaling.

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Induction of RelB Participates in Endotoxin Tolerance

Cited by 101 publications

References 59 publications

Hypoxia-Inducible Factor (HIF) 1α Accumulation and HIF Target Gene Expression Are Impaired after Induction of Endotoxin Tolerance

Hypoxia-Inducible Factor (HIF) 1α Accumulation and HIF Target Gene Expression Are Impaired after Induction of Endotoxin Tolerance

Dynamic and Selective Nucleosome Repositioning during Endotoxin Tolerance

The anti‐TLR4 monoclonal antibody Sa15‐21 enhances inflammatory cytokine production in LPS‐stimulated macrophages

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