Abstract
Monocytes play a central role in the immunopathological effects of sepsis. This role is mediated by production of the cytokines
TNF-a and IL-1ß. The transcription factor NF-E2-related factor 2 (Nrf2) regulates innate immune responses in various experimental
disease models. Presently, the role of Nrf2-regulated genes in LPS-treated human monocytes is not well defined. Herein we
show that Nrf2 mediates a significant regulation of LPS-induced inflammatory responses. Analysis of Nrf2-regulated gene expression
in human monocytes showed that LPS induced the expression of the phase II detoxification gene NAD(P)H:quinone oxidoreductase
1 (NQO1). Furthermore, NQO1 mRNA or protein expression in response to LPS was regulated by Nrf2. Silencing Nrf2 expression
in human monocytes inhibited LPS-induced NQO1 expression; however, in contrast, it significantly increased TNF and IL-1ß production.
Silencing expression of NQO1 alone, or in combination with heme oxygenase-1 (HO-1) silencing, markedly increased LPS-induced
TNF and IL-1ß expression. Additionally, overexpression of NQO1 and/or HO-1 inhibited LPS-induced TNF and IL-1ß expression.
These results show for the first time that LPS induces NQO1 and HO-1 expression in human monocytes via Nrf2 to modulate their
inflammatory responsiveness, thus providing novel potential therapeutic strategies for the treatment of sepsis.
Original language | English |
---|---|
Pages (from-to) | 6730-6737 |
Number of pages | 8 |
Journal | Journal of Immunology |
Volume | 181 |
Publication status | Published - 2008 |