NF-κB c-Rel Dictates the Inflammatory Threshold by Acting as a Transcriptional Repressor

Jesus, Tristan J de; Ramakrishnan, Parameswaran

doi:10.1016/j.isci.2020.100876

Cited by 35 publications

(20 citation statements)

References 85 publications

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“… Activation of NF-κB and regulation of downstream transcriptional antioxidant and pro-oxidant targets in the canonical pathway (adapted from [ 1 , 59 , 80 , 81 , 82 , 83 , 84 ]). …”

Section: Figurementioning

confidence: 99%

Redox Homeostasis in Poultry: Regulatory Roles of NF-κB

2021

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Redox biology is a very quickly developing area of modern biological sciences, and roles of redox homeostasis in health and disease have recently received tremendous attention. There are a range of redox pairs in the cells/tissues responsible for redox homeostasis maintenance/regulation. In general, all redox elements are interconnected and regulated by various means, including antioxidant and vitagene networks. The redox status is responsible for maintenance of cell signaling and cell stress adaptation. Physiological roles of redox homeostasis maintenance in avian species, including poultry, have received limited attention and are poorly characterized. However, for the last 5 years, this topic attracted much attention, and a range of publications covered some related aspects. In fact, transcription factor Nrf2 was shown to be a master regulator of antioxidant defenses via activation of various vitagenes and other protective molecules to maintain redox homeostasis in cells/tissues. It was shown that Nrf2 is closely related to another transcription factor, namely, NF-κB, responsible for control of inflammation; however, its roles in poultry have not yet been characterized. Therefore, the aim of this review is to describe a current view on NF-κB functioning in poultry with a specific emphasis to its nutritional modulation under various stress conditions. In particular, on the one hand, it has been shown that, in many stress conditions in poultry, NF-κB activation can lead to increased synthesis of proinflammatory cytokines leading to systemic inflammation. On the other hand, there are a range of nutrients/supplements that can downregulate NF-κB and decrease the negative consequences of stress-related disturbances in redox homeostasis. In general, vitagene–NF-κB interactions in relation to redox balance homeostasis, immunity, and gut health in poultry production await further research.

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“… Activation of NF-κB and regulation of downstream transcriptional antioxidant and pro-oxidant targets in the canonical pathway (adapted from [ 1 , 59 , 80 , 81 , 82 , 83 , 84 ]). …”

Section: Figurementioning

confidence: 99%

Redox Homeostasis in Poultry: Regulatory Roles of NF-κB

2021

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“…While ABC-DLBCLs are very likely to be associated with RelA activation, the place of c-Rel in DLBCLs remains rather enigmatic since it is associated with GCB-DLBCLs that are not supposed to harbor any NF-kB activity. An explanation for such a discrepancy between the absence of NF-kB signature and REL amplification may have been provided by TJ de Jesùs and P Ramakrishnan (49). Indeed these authors showed that c-Rel represses TNF-a-induced RelA-mediated transcription.…”

Section: Discussionmentioning

confidence: 99%

c-Rel Is the Pivotal NF-κB Subunit in Germinal Center Diffuse Large B-Cell Lymphoma: A LYSA Study

et al. 2021

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Relationships between c-Rel and GCB-DLBCLs remain unclear. We found that strong c-Rel DNA-binding activity was mostly found in GCBs on two independent series of 48 DLBCLs and 66 DLBCLs, the latter issued from the GHEDI series. c-Rel DNA-binding activity was associated with increased REL mRNA expression. Extending the study to the whole GHEDI and Lenz DLBCL published series of 202 and 233 cases, it was found that the c-Rel gene expression profile (GEP) overlapped partially (12%) but only with the GCB GEP and not with the GEP of ABC-DLBCLs. Cases with both overexpression of REL mRNA and c-Rel GEP were defined as those having a c-Rel signature. These cases were GCBs in 88 and 83% of the GHEDI or Lenz’s DLBCL series respectively. The c-Rel signature was also associated with various recurrent GCB-DLBCL genetic events, including REL gains, BCL2 translocation, MEF2B, EZH2, CREBBP, and TNFRSF14 mutations and with the EZB GCB genetic subtype. By CGH array, the c-Rel signature was specifically correlated with 2p15-16.1 amplification that includes XPO1, BCL11A, and USP34 and with the 22q11.22 deletion that covers IGLL5 and PRAME. The total number of gene copy number aberrations, so-called genomic imbalance complexity, was decreased in cases with the c-Rel signature. These cases exhibited a better overall survival. Functionally, overexpression of c-Rel induced its constitutive nuclear localization and protected cells against apoptosis while its repression tended to increase cell death. These results show that, clinically and biologically, c-Rel is the pivotal NF-κB subunit in the GCB-DLBCL subgroup. Functionally, c-Rel overexpression could directly promote DLBCL tumorigenesis without need for further activation signals.

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Section: Discussionmentioning

confidence: 99%

“…Pellet was resuspended in RIPA (EMD Millipore) buffer and sonicated to shear chromatin by using the Sonicator 3000 Ultrasonic liquid processor optimized to 80 cycles of 8-s pulses with an output of 5 that gave a range of DNA fragments from 100 to 1,000 bp, as determined by 2% agarose gel electrophoresis. 49 The soluble chromatin fraction was incubated with either anti-c-Rel antibody or anti-IgG control antibody (Biolegend) coupled to Protein G beads (Cell Signaling) overnight with rotation at 4°C. Immunocomplexes were washed (which was not certified by peer review) is the author/funder.…”

Section: Chromatin Immunoprecipitation (Chip)mentioning

confidence: 99%

NF-kB c-Rel is dispensable for the development but is required for the cytotoxic function of NK cells

Vicioso

Zhang

Ramakrishnan

et al. 2021

Preprint

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Natural Killer (NK) cells are cytotoxic lymphocytes critical to the innate immune system. We found that germline deficiency of NF-kB c-Rel results in a marked decrease in cytotoxic function of NK cells, both in vitro and in vivo, with no significant differences in the stages of NK cell development. We found that c-Rel binds to the promoters of perforin and granzyme B, two key proteins required for NK cytotoxicity, and controls their transactivation. We generated a NK cell specific c-Rel conditional knockout to study NK cell intrinsic role of c-Rel and found that both global and conditional c-Rel deficiency leads to decreased perforin and granzyme B expression and thereby cytotoxic function. We also confirmed the role of c-Rel in perforin and granzyme B expression in human NK cells. c-Rel reconstitution rescued perforin and granzyme B expressions in c-Rel deficient NK cells and restored their cytotoxic function. Our results show a previously unknown role of c-Rel in transcriptional regulation of perforin and granzyme B expressions and control of NK cell cytotoxic function.

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NF-κB c-Rel Dictates the Inflammatory Threshold by Acting as a Transcriptional Repressor

Cited by 35 publications

References 85 publications

Redox Homeostasis in Poultry: Regulatory Roles of NF-κB

Redox Homeostasis in Poultry: Regulatory Roles of NF-κB

c-Rel Is the Pivotal NF-κB Subunit in Germinal Center Diffuse Large B-Cell Lymphoma: A LYSA Study

NF-kB c-Rel is dispensable for the development but is required for the cytotoxic function of NK cells

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