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Lipopolysaccharide-Induced Expression of NAD(P)H:Quinone Oxidoreductase 1 and Heme Oxygenase-1 Protects against Excessive Inflammatory Responses in Human Monocytes

Stuart A. Rushworth^*,, David J. MacEwan^* and Maria A. O'Connell^1,*,

^* School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich, United Kingdom; and Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, United Kingdom

Monocytes play a central role in the immunopathological effects of sepsis. This role is mediated by production of the cytokines TNF- and IL-1β. 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-1β production. Silencing expression of NQO1 alone, or in combination with heme oxygenase-1 (HO-1) silencing, markedly increased LPS-induced TNF and IL-1β expression. Additionally, overexpression of NQO1 and/or HO-1 inhibited LPS-induced TNF and IL-1β 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Maria O'Connell, School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich, NR4 7TJ, United Kingdom. E-mail address: m.oconnell{at}uea.ac.uk

² Abbreviations used in this paper used: Nrf2, NF-E2-related factor 2; ActD, actinomycin D; ARE, antioxidant response element; CHX, cycloheximide; GCLC, glutamyl cysteine ligase catalytic unit; GCLM, glutamyl cysteine ligase modulatory unit; GR, glutathione reductase; H₂DCFDA, 2',7'-dichlorodihydrofluorescein diacetate; HO-1, heme oxygenase-1; NAC, N-acetyl cysteine; NQO1, NAD(P)H:quinone oxidoreductase 1; ROS, reactive oxygen species; siRNA, small interfering RNA; TrxR1, thioredoxin reductase-1.