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

NF-kappa B/Rel family of transcription factors plays a central role in initiation and resolution of inflammatory responses. Here, we identified a function of the NF-kappa B subunit c-Rel as a transcriptional repressor of inflammatory genes. Genetic deletion of c-Rel substantially potentiates the expression of several TNF-alpha-induced RelA-dependent mediators of inflammation. v-Rel, the viral homologue of c-Rel, but not RelB, also possesses this repressive function. Mechanistically, we found that c-Rel selectively binds to the co-repressor HDAC1 and competitively binds to the DNA mediating HDAC1 recruitment to the promoters of inflammatory genes. A specific point mutation at tyrosine(25) in c-Rel's DNA-binding domain, for which a missense single nucleotide variation (Y25H) exists in humans, completely abrogated its ability to bind DNA and repress TNF-alpha-induced, RelA-mediated transcription. Our findings reveal that the transactivator NF-kappa B subunit c-Rel also plays a role as a transcriptional repressor in the maintenance of inflammatory homeostasis.