Dynamic and Selective Nucleosome Repositioning during Endotoxin Tolerance

Gazzar, Mohamed El; Liu, Tiefu; Yoza, Barbara K.; McCall, Charles E.

doi:10.1074/jbc.m109.067330

Cited by 55 publications

(50 citation statements)

References 64 publications

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“…In response to LPS, RelB 2/2 fibroblasts showed prolonged increases in proinflammatory cytokines compared with wild-type controls, suggesting a role for RelB in the resolution of inflammatory responses (43). Finally, RelB was also shown to promote tolerance to LPS, and to diminish proinflammatory responses in macrophages (44,45). These previous findings contrast with the results of the present study, demonstrating that the siRNA-mediated knockdown of RelB diminishes the LPS-induced production of KC, CCL-20, and RANTES.…”

Section: Discussioncontrasting

confidence: 56%

Cooperation between Classical and Alternative NF-κB Pathways Regulates Proinflammatory Responses in Epithelial Cells

Tully

Nolin²,

Guala³

et al. 2012

Am J Respir Cell Mol Biol

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The transcription factor NF-kB has been causally linked to inflammatory lung diseases. Recent studies have unraveled the complexity of NF-kB activation by identifying two parallel activation pathways: the classical NF-kB pathway, which is controlled by IkB kinase complex-b (IKKb) and RelA/p50, and the alternative pathway, which is controlled by IKKa and RelB/p52. The alternative pathway regulates adaptive immune responses and lymphoid development, yet its role in the regulation of innate immune responses remains largely unknown. In this study, we determined the relevance of the alternative NF-kB pathway in proinflammatory responses in lung epithelial cells. The exposure of C10 murine alveolar lung epithelial cells to diverse stimuli, or primary murine tracheal epithelial cells to LPS, resulted in the activation of both NF-kB pathways, based on the nuclear translocation of RelA, p50, RelB, and p52. Increases in the nuclear content of RelA occurred rapidly, but transiently, whereas increases in nuclear RelB content were protracted. The small interfering (si) RNAmediated knockdown of IKKa, RelA, or RelB resulted in decreases of multiple LPS-induced proinflammatory cytokines. Surprisingly, the siRNA ablation of IKKa or RelB led to marked increases in the production of IL-6 in response to LPS. The simultaneous expression of constitutively active (CA)-IKKa and CA-IKKb caused synergistic increases in proinflammatory mediators. Lastly, the disruption of the IKK signalsome inhibited the activation of both NF-kB pathways. These results demonstrate that the coordinated activation of both NF-kB pathways regulates the magnitude and nature of proinflammatory responses in lung epithelial cells.Keywords: lung; IkB kinase-b; IkB kinase-a; RelA; RelB NF-kB is a transcription factor that plays a cardinal role in multiple cellular processes, including survival, proliferation, and inflammation. In unstimulated cells, NF-kB dimers RelA and p50 are sequestered in the cytosol by the inhibitor of kB (IkBa). The IkB kinase complex (IKK) consists of two catalytic subunits, IKKb and IKKa, and the regulatory protein, IKKg (also known as NF-kB essential modulator). Upon ligation by a variety of stimuli such as TNF-a or Toll-like receptor agonists, IKKb is phosphorylated and in turn phosphorylates IkBa, leading to its subsequent ubiquitination and degradation by the 26S proteasome (1, 2). The processing of IkBa promotes the nuclear translocation of RelA/p50, leading to the transcriptional activation of NF-kB-dependent genes. NF-kB activates the transcription of many proinflammatory cytokine and chemokine genes that initiate and propagate innate immune responses (1, 2).The airway epithelium, classically regarded as the first line of defense against inhaled agents, toxic factors, and physical trauma, is now recognized as a key component of the innate immune system, and plays an active role in the orchestration of acute inflammatory and adaptive immune responses (3, 4). Upon stimulation, epithelial cells secrete proinflammatory mediators such as...

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Section: Discussioncontrasting

confidence: 56%

Cooperation between Classical and Alternative NF-κB Pathways Regulates Proinflammatory Responses in Epithelial Cells

Tully

Nolin²,

Guala³

et al. 2012

Am J Respir Cell Mol Biol

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“…As discussed recently (Natoli 2009), nucleosomes in transcription start site-proximal promoter elements may be particularly resistant to NF-kB binding. As a result, Swi/Snf-mediated nucleosome remodeling, independent of NF-kB, may be required for NF-kB binding to some nucleosomal kB DNA sites (Weinmann et al 1999(Weinmann et al , 2001El Gazzar et al 2010) …”

Section: Ptms Influence Coregulator Recruitmentmentioning

confidence: 99%

NF-κB, the first quarter-century: remarkable progress and outstanding questions

Hayden¹,

Ghosh²

2012

Genes Dev.

1,495

1,576

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The ability to sense and adjust to the environment is crucial to life. For multicellular organisms, the ability to respond to external changes is essential not only for survival but also for normal development and physiology. Although signaling events can directly modify cellular function, typically signaling acts to alter transcriptional responses to generate both transient and sustained changes. Rapid, but transient, changes in gene expression are mediated by inducible transcription factors such as NF-κB. For the past 25 years, NF-κB has served as a paradigm for inducible transcription factors and has provided numerous insights into how signaling events influence gene expression and physiology. Since its discovery as a regulator of expression of the κ light chain gene in B cells, research on NF-κB continues to yield new insights into fundamental cellular processes. Advances in understanding the mechanisms that regulate NF-κB have been accompanied by progress in elucidating the biological significance of this transcription factor in various physiological processes. NF-κB likely plays the most prominent role in the development and function of the immune system and, not surprisingly, when dysregulated, contributes to the pathophysiology of inflammatory disease. As our appreciation of the fundamental role of inflammation in disease pathogenesis has increased, so too has the importance of NF-κB as a key regulatory molecule gained progressively greater significance. However, despite the tremendous progress that has been made in understanding the regulation of NF-κB, there is much that remains to be understood. In this review, we highlight both the progress that has been made and the fundamental questions that remain unanswered after 25 years of study.

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“…Impact of transcription on H2A.Z and H3K4m3 expression: exploration with actinomycin D. Changes in histone expression can be a cause or a result of increased gene transcription (6,7,10,11,14,17,19). Thus we assessed whether transcription, per se, impacts Feinduced H2A.Z and H3K4m3 changes at the four target genes.…”

Section: Cell Culture Experimentsmentioning

confidence: 99%