Nrf2-mediated anti-inflammation through transcriptional repression of proinflammatory cytokine genesNrf2-mediated anti-inflammation through transcriptional repression of proinflammatory cytokine genes. Mus musculus

Nrf2 (NF-E2-related factor-2) transcription factor regulates oxidative/xenobiotic stress response and also represses inflammation. However, the mechanisms how Nrf2 alleviates inflammation are still unclear. Here, we demonstrate that Nrf2 directly represses lipopolysaccharide-induced transcription of proinflammatory cytokines, including IL-6 and IL-1. ChIP-seq analysis revealed that Nrf2 binds to the proximity of these genes in macrophages and inhibits RNA Pol II recruitment. An in vivo model demonstrated that Nrf2 represses IL6 expression and inflammatory phenotypes. Thus, contrary to the widely accepted view that Nrf2 is a transcription activator, we demonstrated that Nrf2 represses inflammation through direct transcriptional repression of proinflammatory genes. This study identifies Nrf2 as the upstream regulator of cytokine production and establishes a novel molecular basis for an Nrf2-mediated anti-inflammation approach.