Endotoxin Tolerance Disrupts Chromatin Remodeling and NF-κB Transactivation at the IL-1β Promoter

Chan, Cora; Li, Liwu; McCall, Charles E.; Yoza, Barbara K.

doi:10.4049/jimmunol.175.1.461

Cited by 164 publications

(163 citation statements)

References 54 publications

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“…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: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Transcriptional activation of the IL-1␤ and iNOS promoters by LPS is dependent on binding sites for NF-B proteins in regulatory regions (27,28). To investigate whether FXR ligands alter the expression of these genes in a promoter-dependent manner, transactivation experiments were conducted on FXR-negative, TLR-4 expressing HEK293 cells (HEK293-TLR-4) transfected with a luciferase reporter plasmid under the transcriptional control of the IL-1␤ and iNOS promoter regions containing an NF-B response element.…”

Section: M)mentioning

confidence: 99%

The Bile Acid Receptor FXR Is a Modulator of Intestinal Innate Immunity

Vavassori

Mencarelli²,

Renga³

et al. 2009

The Journal of Immunology

514

442

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The farnesoid X receptor (FXR) is a bile acid-regulated nuclear receptor expressed in enterohepatic tissues. In this study we investigated whether FXR is expressed by cells of innate immunity and regulates inflammation in animal models of colitis. Acute (7 days) and chronic (8 wk) colitis were induced in wild-type and FXR−/− mice by intrarectal administration of trinitrobenzensulfonic acid or by 7-day administration of 5% dextran sulfate in drinking water. The results of this experiment demonstrate that FXR is expressed by and exerts counterregulatory effects on cells of innate immunity. Exposure of LPS-activated macrophages to 6-ethyl chenodeoxycholic acid (6E-CDCA; INT-747) a synthetic FXR ligand, results in a reciprocal regulation of NF-κB dependent-genes (TNF-α, IL-1β, IL-6, COX-1, COX-2, and iNOS) and induction of SHP, a FXR-regulated gene. FXR activation stabilizes the nuclear corepressor NCoR on the NF-κB responsive element on the IL-1β promoter. Colon inflammation in Crohn’s disease patients and in rodent models of colitis is associated with a reduced expression of FXR mRNA. Using two rodent models of colon inflammation, we show that progression of these immune-mediated disorders is exacerbated in FXR−/− mice (p < 0.01). In vivo treatment with INT-747 attenuates organ injury and immune cell activation. FXR activation increased the colon expression of I-BABP, FXR, and SHP while reducing IL-1β, IL-2, IL-6, TNF-α, and IFN-γ mRNA expression and attenuating disease severity. In aggregate, these findings provide evidence that FXR is an essential component of a network of nuclear receptors that regulate intestinal innate immunity and homeostasis.

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“…Moreover, IL-1b has long been linked to the pathogenesis of atherosclerosis and rheumatoid arthritis diseases [12][13][14] . The cytokine IL-1b is mostly produced by activated monocytes, macrophages, and primary dendritic cells (DCs) mainly through a NF-kB-dependent pathway 15,16 . The expression of IL-1 is regulated at the levels of transcription, mRNA stabilization, and post-translational proteolytic processing 14 .…”

Section: Introductionmentioning

confidence: 99%

TSC1 controls IL-1β expression in macrophages via mTORC1-dependent C/EBPβ pathway

et al. 2015

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The tuberous sclerosis complex 1 (TSC1) is a tumor suppressor that inhibits the mammalian target of rapamycin (mTOR), which serves as a key regulator of inflammatory responses after bacterial stimulation in monocytes, macrophages, and primary dendritic cells. Previous studies have shown that TSC1 knockout (KO) macrophages produced increased inflammatory responses including tumor necrosis factor-a (TNF-a) and IL-12 to pro-inflammatory stimuli, but whether and how TSC1 regulates pro-IL-1b expression remains unclear. Here using a mouse model in which myeloid lineage-specific deletion of TSC1 leads to constitutive mTORC1 activation, we found that TSC1 deficiency resulted in impaired expression of pro-IL-1b in macrophages following lipopolysaccharide stimulation. Such decreased pro-IL-1b expression in TSC1 KO macrophages was rescued by reducing mTORC1 activity with rapamycin or deletion of mTOR. Rictor deficiency has no detectable effect on pro-IL-1b synthesis, suggesting that TSC1 positively controls pro-IL-1b expression through mTORC1 pathway. Moreover, mechanism studies suggest that mTORC1-mediated downregulation of the CCAAT enhancer-binding protein (C/EBPb) critically contributes to the defective pro-IL-1b expression. Overall, these findings highlight a critical role of TSC1 in regulating innate immunity by control of the mTOR1-C/EBPb pathway. Cellular & Molecular Immunology

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Endotoxin Tolerance Disrupts Chromatin Remodeling and NF-κB Transactivation at the IL-1β Promoter

Cited by 164 publications

References 54 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

The Bile Acid Receptor FXR Is a Modulator of Intestinal Innate Immunity

TSC1 controls IL-1β expression in macrophages via mTORC1-dependent C/EBPβ pathway

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