Role of p52 (NF-kappaB2) in LPS Tolerance in a Human B Cell Line

Wedel, Andrew; Frankenberger, Marion; Sulski, G.; Petersmann, I; Kuprash, Dmitry V.; Nedospasov, Sergei A.; Ziegler‐Heitbrock, H. W. L.

doi:10.1515/bc.1999.151

Cited by 20 publications

(12 citation statements)

References 45 publications

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“…Recently, it was confirmed that NF-B regulates HIF-1␣ at the transcriptional level (14). Wedel et al (33) analyzed the role of different members of the transcription factor NF-B superfamily for the induction of endotoxin tolerance in more detail. They found an up-regulation of the p52 protein and its precursor p100/RelB after induction of LPS tolerance in a human B cell line.…”

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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“…In addition, we have previously shown that CD4 ϩ T cells from mice tolerized in vivo express qualitative alterations in the composition of the NF B complex (13). Defective NF B expression is also a feature of tolerant B cells (14,15).The NF B family consists of five members, p65, c-rel, RelB, p105/p50, and p100/p52, and the NF B complex is formed by hetero-or homodimerization of these different proteins (16). p65, c-rel, and RelB are synthesized as mature proteins and contain transactivation domains, whereas p105/p50 and p100/ p52 are produced as inactive precursor proteins and lack transactivation domains.…”

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confidence: 99%

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confidence: 99%

Bcl-3 and NFκB p50-p50 Homodimers Act as Transcriptional Repressors in Tolerant CD4+ T Cells

Grundström

Anderson

Scheipers

et al. 2004

Journal of Biological Chemistry

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The transcriptional events that control T cell tolerance are still poorly understood. To investigate why tolerant T cells fail to produce interleukin (IL)-2, we analyzed the regulation of NF B-mediated transcription in CD4 ؉ T cells after tolerance induction in vivo. We demonstrate that a predominance of p50-p50 homodimers binding to the IL-2 promoter B site in tolerant T cells correlated with repression of NF B-driven transcription. Impaired translocation of the p65 subunit in tolerant T cells was a result from reduced activation of I B kinase and poor phosphorylation and degradation of cytosolic I Bs. Moreover, tolerant T cells expressed high amounts of the p50 protein. However, the increased expression of p50 could not be explained by activation-induced de novo synthesis of the precursor p105, which was constitutively expressed in tolerant T cells. We also demonstrate the exclusive induction of the I B protein B cell lymphoma 3 (Bcl-3) in tolerant T cells as well as its specific binding to the NF B site. These results suggest that the cellular ratio of NF B dimers, and thus the repression of NF B activity and IL-2 production, are regulated at several levels in tolerant CD4 ؉ T cells in vivo.Induction of T cell tolerance may result in either deletion or anergy, the latter being characterized by a block in proliferation and diminished expression of Th1 cytokines, particularly interleukin-2 (IL-2) 1 (1). Although T cell anergy has been described both in vitro and in vivo (2-5), recent studies have shown that rather than being functionally inert, the anergic T cells may adopt the role of regulatory T cells with a Tr1-like phenotype (6, 7). Importantly, anergic T cells may be functionally regulated at several different levels, e.g. in vivo tolerized T cells may neither produce IL-2 nor respond to signaling through the IL-2 receptor (8).Because the failure of tolerant T cells to produce IL-2 is a hallmark of anergy, it is particularly important to delineate the molecular explanation for this defect. Downstream of the T cell receptor (TCR), several intracellular signaling pathways converge at the level of transcriptional regulation of the IL-2 gene. AP-1, NFAT, and NF B families of transcription factors are essential in T cell activation as coordinators of IL-2 transcription (9) and tolerant CD4 ϩ T cell clones as well as in vivo tolerized T cells possess reduced AP-1 binding to the IL-2 promoter (10 -12). In addition, we have previously shown that CD4 ϩ T cells from mice tolerized in vivo express qualitative alterations in the composition of the NF B complex (13). Defective NF B expression is also a feature of tolerant B cells (14,15).The NF B family consists of five members, p65, c-rel, RelB, p105/p50, and p100/p52, and the NF B complex is formed by hetero-or homodimerization of these different proteins (16). p65, c-rel, and RelB are synthesized as mature proteins and contain transactivation domains, whereas p105/p50 and p100/ p52 are produced as inactive precursor proteins and lack transactivation domains. Activa...

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“…The mechanisms underlying the induction of macrophage tolerance have been the subject of intense study, particularly with respect to TLR ligands. Some of the mechanisms that have been implicated in this process include down-regulation of TLR4 (37); decreased expression of postreceptor signaling molecules, such as the interleukin-1 receptor-associated kinase (IRAK) (32); alterations in the association between TLR5 and downstream signaling molecules (34); increased expression of proteins that block TLR signal transduction, such as IRAK-M, the macrophage-specific, kinase-deficient member of the IRAK family (27), and SOCS-1 (suppressor of cytokine signaling 1) (26,36); and, finally, upregulation of the p50 and p52 subunits of the NF-B transcription factor (24,51). Although the exact physiologic significance of macrophage tolerance is not clear, it may be important in limiting the extent and duration of inflammatory responses.…”

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Role of Toll-Like Receptor 4 in Macrophage Activation and Tolerance duringSalmonella entericaSerovar Typhimurium Infection

Cherayil

2003

Infect Immun

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Toll-like receptors (TLRs) play an important role in the innate immune response, particularly in the initial interaction between the infecting microorganism and phagocytic cells, such as macrophages. We investigated the role of TLR4 during infection of primary murine peritoneal macrophages with Salmonella enterica serovar Typhimurium. We found that macrophages from the C3H/HeJ mouse strain, which carries a functionally inactive Tlr4 gene, exhibit marked impairment of tumor necrosis factor alpha (TNF-␣) secretion in response to S. enterica serovar Typhimurium infection. However, activation of extracellular growth factor-regulated kinase and NF-B signaling pathways was relatively unaffected, as was increased expression of TNF-␣ mRNA. Furthermore, macrophage tolerance, which is associated with increased expression of the NF-B p50 and p52 subunits, was induced by S. enterica serovar Typhimurium even in the absence of functional TLR4. These results indicate that during infection of macrophages by S. enterica serovar Typhimurium, TLR4 signals are required at a posttranscriptional step to maximize secretion of TNF-␣. Signals delivered by pattern recognition receptors other than TLR4 are sufficient for the increased expression of the TNF-␣ transcript and at least some genes associated with macrophage tolerance.

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Role of p52 (NF-kappaB2) in LPS Tolerance in a Human B Cell Line

Cited by 20 publications

References 45 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

Bcl-3 and NFκB p50-p50 Homodimers Act as Transcriptional Repressors in Tolerant CD4+ T Cells

Role of Toll-Like Receptor 4 in Macrophage Activation and Tolerance duringSalmonella entericaSerovar Typhimurium Infection

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