LB982 Novel mechanism of self inhibition by NF-κB c-Rel

Abstract

Dimers of the NF-κB/Rel transcription factor family regulate a wide range of cellular processes ranging from cytokine production and inflammation to cell survival and proliferation. Each of the fifteen possible NF-κB dimers exhibit slight differences in κB-site specificity, and thus have different target gene expression profiles. Although NF-κB dimer specificity has been somewhat well studied, the mechanisms regulating dimer specific NF-κB transactivation after its translocation into the nucleus is as of now fairly opaque. We have identified a novel mechanism by which NF-κB c-Rel can cross-regulate another NF-κB family member, p65 (RelA). In both mouse embryonic fibroblasts as well as keratinocytes, the absence of c-Rel greatly increases TNF-α-induced p65-targeted gene expression. This is accompanied by both an increase in p65 nuclear translocation and activation. Cross-inhibition of inflammatory gene expression by subunits that are classically thought to be transactivators have interesting implications on many pathologies, including those affecting the skin. Our findings demonstrate a novel role of c-Rel in the suppression of the pro-inflammatory NF-κB profile, and have begun to elucidate a mechanism by which this inhibition occurs, and in the future may provide new therapeutic targets for interfering or encouraging dimer specific interactions of NF-κB.