Coordinate regulation of enzyme markers for inflammation and for protection against oxidants and electrophiles

Hua Liu, Albena T. Dinkova-Kostova, Paul Talalay (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    104 Citations (Scopus)

    Abstract

    An elaborate network of highly inducible phase 2 proteins protects aerobic cells against the cumulative damaging effects of reactive oxygen intermediates and toxic electrophiles, which are the major causes of malignancy and chronic degenerative diseases. Many chemical and phytochemical agents, all of which react with thiol groups, induce the phase 2 response through their reactivity with critical cysteine thiols of Keap1. We recently found that the anti-inflammatory potencies (suppression of NOS and COX-2 expression) of a series of triterpenoids with Michael reaction centers were closely correlated with the potencies of these agents to induce the phase 2 response. We now report that representatives of seven recognized chemical classes of inducers, including isothiocyanates, bisbenzylidenes, arsenicals, heavy metals, and vicinal dithiols, showed highly correlated inducer and anti-inflammatory potencies spanning more than six orders of magnitude of concentrations in established cells and in primary mouse peritoneal macrophages. Potency measurements were expressed as the D-m values (median effect concentration) by use of the Median Effect Equation. Whereas the phase 2 induction required the functional integrity of both the repressor Keap1 and the transcription factor Nrf2, the effectiveness of inducers in blocking the up-regulation of NOS by inflammatory cytokines was related to the nature of the cytokine and the inducer concentration. These studies identify suppression of inflammation as a consistent property of inducers of the phase 2 response and strongly suggest that this property is a central aspect of their chemoprotective actions.

    Original languageEnglish
    Pages (from-to)15926-15931
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume105
    Issue number41
    DOIs
    Publication statusPublished - 14 Oct 2008

    Keywords

    • Keap1
    • NAD(P)H:quinone oxidoreductase
    • Nrf2
    • sulforaphane
    • inducible NOS
    • NF-KAPPA-B
    • PIGMENT EPITHELIAL-CELLS
    • NRF2 ENHANCES SUSCEPTIBILITY
    • MICHAEL REACTION ACCEPTORS
    • TRANSCRIPTION FACTOR
    • OXIDATIVE STRESS
    • GENE-EXPRESSION
    • QUINONE REDUCTASE
    • SULFHYDRYL-GROUPS
    • DIRECT INHIBITION

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