Lipopolysaccharide-induced expression of NAD(P)H:quinone oxidoreductase 1 and heme oxygenase-1 protects against excessive inflammatory responses in human monocytes.
Monocytes play a central role in the immunopathological effects of sepsis. This role is mediated by production of the cytokines TNF-alpha and IL-1beta. 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-1beta production. Silencing expression of NQO1 alone, or in combination with heme oxygenase-1 (HO-1) silencing, markedly increased LPS-induced TNF and IL-1beta expression. Additionally, overexpression of NQO1 and/or HO-1 inhibited LPS-induced TNF and IL-1beta 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.
Rushworth
Stuart A
SA
School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich, United Kingdom.
MacEwan
David J
DJ
O'Connell
Maria A
MA
D002460:Cell Line; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology*; D020868:Gene Silencing; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human