scholarly journals NF-κB dynamics determine the stimulus specificity of epigenomic reprogramming in macrophages

Science ◽  
2021 ◽  
Vol 372 (6548) ◽  
pp. 1349-1353
Author(s):  
Quen J. Cheng ◽  
Sho Ohta ◽  
Katherine M. Sheu ◽  
Roberto Spreafico ◽  
Adewunmi Adelaja ◽  
...  
Keyword(s):  
Immune Response ◽  
Transcription Factor ◽  
Temporal Dynamics ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Dna Interactions ◽  
Specific Manner ◽  
Epigenomic Reprogramming ◽  
Nucleosomal Histone ◽  
Stimulus Specificity

The epigenome of macrophages can be reprogrammed by extracellular cues, but the extent to which different stimuli achieve this is unclear. Nuclear factor κB (NF-κB) is a transcription factor that is activated by all pathogen-associated stimuli and can reprogram the epigenome by activating latent enhancers. However, we show that NF-κB does so only in response to a subset of stimuli. This stimulus specificity depends on the temporal dynamics of NF-κB activity, in particular whether it is oscillatory or non-oscillatory. Non-oscillatory NF-κB opens chromatin by sustained disruption of nucleosomal histone–DNA interactions, enabling activation of latent enhancers that modulate expression of immune response genes. Thus, temporal dynamics can determine a transcription factor’s capacity to reprogram the epigenome in a stimulus-specific manner.

scholarly journals Endoplasmic reticulum and oxidant stress mediate nuclear factor-κB activation in the subfornical organ during angiotensin II hypertension

2015 ◽  
Vol 308 (10) ◽  
pp. C803-C812 ◽  
Author(s):  
Colin N. Young ◽  
Anfei Li ◽  
Frederick N. Dong ◽  
Julie A. Horwath ◽  
Catharine G. Clark ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Angiotensin Ii ◽  
Er Stress ◽  
Bioluminescence Imaging ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Ang Ii ◽  
Arterial Blood

Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation in the brain circumventricular subfornical organ (SFO) mediate the central hypertensive actions of Angiotensin II (ANG II). However, the downstream signaling events remain unclear. Here we tested the hypothesis that angiotensin type 1a receptors (AT1aR), ER stress, and ROS induce activation of the transcription factor nuclear factor-κB (NF-κB) during ANG II-dependent hypertension. To spatiotemporally track NF-κB activity in the SFO throughout the development of ANG II-dependent hypertension, we used SFO-targeted adenoviral delivery and longitudinal bioluminescence imaging in mice. During low-dose infusion of ANG II, bioluminescence imaging revealed a prehypertensive surge in NF-κB activity in the SFO at a time point prior to a significant rise in arterial blood pressure. SFO-targeted ablation of AT1aR, inhibition of ER stress, or adenoviral scavenging of ROS in the SFO prevented the ANG II-induced increase in SFO NF-κB. These findings highlight the utility of bioluminescence imaging to longitudinally track transcription factor activation during the development of ANG II-dependent hypertension and reveal an AT1aR-, ER stress-, and ROS-dependent prehypertensive surge in NF-κB activity in the SFO. Furthermore, the increase in NF-κB activity before a rise in arterial blood pressure suggests a causal role for SFO NF-κB in the development of ANG II-dependent hypertension.

scholarly journals Mitochondrial reactive oxygen species regulate the temporal activation of nuclear factor κB to modulate tumour necrosis factor-induced apoptosis: evidence from mitochondria-targeted antioxidants

2005 ◽  
Vol 389 (1) ◽  
pp. 83-89 ◽  
Author(s):  
Gillian HUGHES ◽  
Michael P. MURPHY ◽  
Elizabeth C. LEDGERWOOD
Keyword(s):  
Reactive Oxygen Species ◽  
Transcription Factor ◽  
Tumour Necrosis ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Oxygen Species ◽  
Mitochondrial Matrix ◽  
Mitochondrial Ros ◽  
Induced Apoptosis ◽  
Necrosis Factor

ROS (reactive oxygen species) from mitochondrial and non-mitochondrial sources have been implicated in TNFα (tumour necrosis factor α)-mediated signalling. In the present study, a new class of specific mitochondria-targeted antioxidants were used to explore directly the role of mitochondrial ROS in TNF-induced apoptosis. MitoVit E {[2-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)ethyl]triphenylphosphonium bromide} (vitamin E attached to a lipophilic cation that facilitates accumulation of the antioxidant in the mitochondrial matrix) enhanced TNF-induced apoptosis of U937 cells. In time course analyses, cleavage and activation of caspase 8 in response to TNF were not affected by MitoVit E, whereas the activation of caspase 3 was significantly increased. Furthermore, there was an increased cleavage of the proapoptotic Bcl-2 family member Bid and an increased release of cytochrome c from mitochondria, in cells treated with TNF in the presence of MitoVit E. We considered several mechanisms by which MitoVit E might accelerate TNF-induced apoptosis including mitochondrial integrity (ATP/ADP levels and permeability transition), alterations in calcium homoeostasis and transcription factor activation. Of these, only the transcription factor NF-κB (nuclear factor κB) was implicated. TNF caused maximal nuclear translocation of NF-κB within 15 min, compared with 1 h in cells pretreated with MitoVit E. Thus the accumulation of an antioxidant within the mitochondrial matrix enhances TNF-induced apoptosis by decreasing or delaying the expression of the protective antiapoptotic proteins. These results demonstrate that mitochondrial ROS production is a physiologically relevant component of the TNF signal-transduction pathway during apoptosis, and reveal a novel functional role for mitochondrial ROS as a temporal regulator of NF-κB activation and NF-κB-dependent antiapoptotic signalling.

Upregulated Signaling Pathways in Ruptured Human Saccular Intracranial Aneurysm Wall: An Emerging Regulative Role of Toll-Like Receptor Signaling and Nuclear Factor-κB, Hypoxia-Inducible Factor-1A, and ETS Transcription Factors

Neurosurgery ◽  
2011 ◽  
Vol 68 (6) ◽  
pp. 1667-1676 ◽  
Author(s):  
Mitja I. Kurki ◽  
Sanna-Kaisa Häkkinen ◽  
Juhana Frösen ◽  
Riikka Tulamo ◽  
Mikael von und zu Fraunberg ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Intracranial Aneurysm ◽  
Signaling Pathways ◽  
Binding Sites ◽  
Hypoxia Inducible Factor ◽  
Transcription Factor Binding Sites ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Toll Like Receptor ◽  
Factor Binding

Abstract BACKGROUND: Aneurysmal subarachnoid hemorrhage, almost always from saccular intracranial aneurysm (sIA), is a devastating form of stroke that affects the working-age population. Cellular and molecular mechanisms predisposing to the rupture of the sIA wall are largely unknown. This knowledge would facilitate the design of novel diagnostic tools and therapies for the sIA disease. OBJECTIVE: To investigate gene expression patterns distinguishing ruptured and unruptured sIA. METHODS: We compared the whole-genome expression profile of 11 ruptured sIA wall samples with that of 8 unruptured ones using oligonucleotide microarrays. Signaling pathways enriched in the ruptured sIA walls were identified with bioinformatic analyses. Their transcriptional control was predicted in silico by seeking the enrichment of conserved transcription factor binding sites in the promoter regions of differentially expressed genes. RESULTS: Overall, 686 genes were significantly upregulated and 740 were downregulated in the ruptured sIA walls. Significantly upregulated biological processes included response to turbulent blood flow, chemotaxis, leukocyte migration, oxidative stress, vascular remodeling; and extracellular matrix degradation. Toll-like receptor signaling and nuclear factor-κB, hypoxia-inducible factor-1A, and ETS transcription factor binding sites were significantly enriched among the upregulated genes. CONCLUSION: We identified pathways and candidate genes associated with the rupture of human sIA wall. Our results may provide clues to the molecular mechanism in sIA wall rupture and insight for novel therapeutic strategies to prevent rupture.

scholarly journals Inhibition of Nuclear Factor-κB or Bax Prevents Endoplasmic Reticulum Stress- But Not Nitric Oxide-Mediated Apoptosis in INS-1E Cells

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4094-4103 ◽  
Author(s):  
Morten F. Tonnesen ◽  
Lars G. Grunnet ◽  
Josefine Friberg ◽  
Alessandra K. Cardozo ◽  
Nils Billestrup ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Transcription Factor ◽  
Er Stress ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Β Cell ◽  
No Donor ◽  
Homologous Protein ◽  
Enhancer Binding Protein

Abstract Accumulating evidence suggests that endoplasmic reticulum (ER) stress by mechanisms that include ER Ca2+ depletion via NO-dependent down-regulation of sarcoendoplasmic reticulum Ca2+ ATPase 2b (SERCA2b) contributes to β-cell death in type 1 diabetes. To clarify whether the molecular pathways elicited by NO and ER Ca2+ depletion differ, we here compare the direct effects of NO, in the form of the NO donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP), with the effects of SERCA2 inhibitor thapsigargin (TG) on MAPK, nuclear factor κB (NFκB), Bcl-2 proteins, ER stress, and apoptosis. Exposure of INS-1E cells to TG or SNAP caused caspase-3 cleavage and apoptosis. Both TG and SNAP induced activation of the proapoptotic transcription factor CCAAT/enhancer-binding protein homologous protein (CHOP). However, other classical ER stress-induced markers such as up-regulation of ER chaperone Bip and alternative splicing of the transcription factor Xbp-1 were exclusively activated by TG. TG exposure caused NFκB activation, as assessed by IκB degradation and NFκB DNA binding. Inhibition of NFκB or the Bcl-2 family member Bax pathways protected β-cells against TG- but not SNAP-induced β-cell death. These data suggest that NO generation and direct SERCA2 inhibition cause two quantitative and qualitative different forms of ER stress. In contrast to NO, direct ER stress induced by SERCA inhibition causes activation of ER stress signaling pathways and elicit proapoptotic signaling via NFκB and Bax.

scholarly journals NFAT5 Contributes to Osmolality-Induced MCP-1 Expression in Mesothelial Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Christoph Küper ◽  
Franz-X. Beck ◽  
Wolfgang Neuhofer
Keyword(s):  
Transcription Factor ◽  
Mesothelial Cell ◽  
Nuclear Factor Κb ◽  
Mesothelial Cells ◽  
Nuclear Factor ◽  
Peritoneal Fibrosis ◽  
Activated T Cells ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Transcription Factor Nuclear Factor

Increased expression of the C-C chemokine monocyte chemoattractant protein-1 (MCP-1) in mesothelial cells in response to high glucose concentrations and/or high osmolality plays a crucial role in the development of peritoneal fibrosis during continuous ambulatory peritoneal dialysis (CAPD). Recent studies suggest that in kidney cells osmolality-induced MCP-1 upregulation is mediated by the osmosensitive transcription factor, nuclear factor of activated T cells 5 (NFAT5). The present study addressed the question of whether activation of NFAT5 by hyperosmolality, as present in PD fluids, contributes to MCP-1 expression in the mesothelial cell line Met5A. Hyperosmolality, induced by addition of glucose, NaCl, or mannitol to the growth medium, increased NFAT5 activity and stimulated MCP-1 expression in Met5A cells. siRNA-mediated knockdown of NFAT5 attenuated osmolality-induced MCP-1 upregulation substantially. Hyperosmolality also induced activation of nuclear factor-κB (NF-κB). Accordingly, pharmacological inhibition of NF-κB significantly decreased osmolality-induced MCP-1 expression. Taken together, these results indicate that high osmolalities activate the transcription factor NFAT5 in mesothelial cells. NFAT5 in turn upregulates MCP-1, likely in combination with NF-κB, and thus may participate in the development of peritoneal fibrosis during CAPD.

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