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Electrophilic Nrf2 activators and itaconate inhibit inflammation at low dose and promote IL-1? production and inflammatory apoptosis at high dose.

ABSTRACT: Controlling inflammation is critical for preventing many diseases including cancer, autoimmune disorders and hypersensitivity reactions. NF-E2-related factor 2 (Nrf2) is a key transcription factor that controls the cellular antioxidant and cytoprotective response. Moreover, Nrf2 has been implicated in the regulation of inflammatory processes, although the ultimate mechanism by which this is achieved is unknown. Here, we investigated mechanisms of inflammation and cell death pathways induced by a variety of Nrf2 activators including dimethyl fumarate (DMF) and the endogenous metabolite itaconate. We found that exposure of bone marrow-derived dendritic cells (BMDCs) to low concentrations of a variety of electrophilic Nrf2 activators including itaconate prior to Toll-like receptor (TLR) stimulation inhibits transcription of pro-inflammatory cytokines (such as interleukin [IL]-12 and IL-1?) by activation of Nrf2. By contrast, high doses of these electrophilic compounds after TLR activation promote inflammatory apoptosis and caspase-8-dependent IL-1? processing and release independently of Nrf2. Interestingly, tert-butylhydroquinone (tBHQ), a non-electrophilic Nrf2-activator, failed to induce IL-1? production. These results have important implications for clinical application of electrophilic compounds.

SUBMITTER: Muri J

PROVIDER: S-EPMC7387846 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Electrophilic Nrf2 activators and itaconate inhibit inflammation at low dose and promote IL-1β production and inflammatory apoptosis at high dose.

Muri Jonathan J Wolleb Helene H Broz Petr P Carreira Erick M EM Kopf Manfred M

Redox biology 20200721

Controlling inflammation is critical for preventing many diseases including cancer, autoimmune disorders and hypersensitivity reactions. NF-E2-related factor 2 (Nrf2) is a key transcription factor that controls the cellular antioxidant and cytoprotective response. Moreover, Nrf2 has been implicated in the regulation of inflammatory processes, although the ultimate mechanism by which this is achieved is unknown. Here, we investigated mechanisms of inflammation and cell death pathways induced by a ...[more]

PMID: 32863237

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Dataset Information

Electrophilic Nrf2 activators and itaconate inhibit inflammation at low dose and promote IL-1? production and inflammatory apoptosis at high dose.

Publications

Electrophilic Nrf2 activators and itaconate inhibit inflammation at low dose and promote IL-1β production and inflammatory apoptosis at high dose.

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