TNF- and IL-1-induced inflammation are enhanced through cooperative interactions between Nrf2 and NF-κB.

Abstract

Reactive oxygen species are typically elevated at inflammatory sites due to influx of large numbers of neutrophils and other myeloid cells that produce oxygen free radicals as microbicidal agents. However, although oxidative stress is frequently implicated as an initiator or amplifier of inflammation, particularly in the context of cancer, the key mediators of reactive oxygen-driven inflammation require clarification. Here we show that the redox-responsive transcription factor, Nrf2, can act as an enhancer of TNF- and IL-1-initiated inflammation. Silencing or deletion of the Nrf2 antagonist, Keap1, led to robustly enhanced TNF- or IL-1-driven inflammatory cytokine production. Conversely, suppression of Nrf2 activation blunted inflammation in the same contexts. Mechanistically, Nrf2 enhanced inflammation through cooperative interactions with p65 RelA at NFκB-regulated promoters. These observations reveal a direct link between the Keap1/Nrf2 reactive oxygen-sensing pathway and TNF- or IL-1-initiated inflammation and suggest that Nrf2 can act as a rheostat for NFκB-dependent inflammatory outputs.

Key Findings

• Nrf2 acts as an enhancer of TNF- and IL-1-initiated inflammation.
• Silencing or deletion of Keap1, an antagonist of Nrf2, leads to increased inflammatory cytokine production.
• Nrf2 enhances inflammation through cooperative interactions with p65 RelA at NFκB-regulated promoters.

Clinical Significance

Citation

Costigan Aoife, Gunay Gokhan, Venugopalan Vaishnaviet al.. TNF- and IL-1-induced inflammation are enhanced through cooperative interactions between Nrf2 and NF-κB. Cell reports. 2026-Nov-06.