Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-imidazolide

被引:313
作者
Thimmulappa, Rajesh K.
Scollick, Catherine
Traore, Kassim
Yates, Melinda
Trush, Michael A.
Liby, Karen T.
Sporn, Michael B.
Yamamoto, Masayuki
Kensler, Thomas W.
Biswal, Shyam [1 ]
机构
[1] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21218 USA
[2] Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Baltimore, MD 21218 USA
[3] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD 21218 USA
[4] Dartmouth Coll Sch Med, Dept Pharmacol & Toxicol, Hanover, NH USA
[5] Univ Tsukuba, Ctr Tsukuba Adv Res Alliance, Tsukuba, Ibaraki 305, Japan
[6] Univ Tsukuba, Inst Basic Med Sci, Tsukuba, Ibaraki 305, Japan
关键词
Nrf2; CDDO-Im; neutrophils; macrophages; innate immune response; antioxidant; ROS;
D O I
10.1016/j.bbrc.2006.10.102
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Sepsis induced lethality is characterized by amplified host innate immune response. Nrf2, a bZIP transcription factor, regulates a battery of cellular antioxidative genes and maintains cellular redox homeostasis. This study demonstrates that increasing Nrf2 activity by a potent small molecule activator, CDDO-Im (1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole), protects from deregulation of lipopolysaccharide (LPS) induced innate immune response. In response to LPS stimuli, nrf2-deficient (nrf2 -/-) peritoneal neutrophils showed increased NADPH oxidase-dependent ROS generation, proinflammatory cytokines (Tnf-alpha and Il-6) and chemokines (Mip2 and Mcp-1) relative to wild-type (nrf2 +/+) cells. Pretreatment of peritoneal neutrophils with CDDO-Im induced antioxidative genes (Ho-1, Gclc, Gclm, and Nqo1) and attenuated LPS induced ROS generation as well as expression of proinflammatory cytokines exclusively in nrf2 +/+ neutrophils but not in nrf2 -/- cells. In corroboration with in vitro studies, pretreatment with CDDO-Im induced Nrf2-dependent antioxidative genes, attenuated LPS induced proinflammatory cytokine expression, and decreased mortality specifically in the nrf2 +/+ mice. In conclusion, the results suggest that Nrf2 is associated with oxidative regulation of LPS induced innate immune response in neutrophils. Activation of Nrf2-dependent compensatory antioxidative pathways by CDDO-Im protects from LPS induced inflammatory response and mortality. (c) 2006 Elsevier Inc. All rights reserved.
引用
收藏
页码:883 / 889
页数:7
相关论文
共 18 条
[1]   Involvement of reactive oxygen species in Toll-like receptor 4-dependent activation of NF-κB [J].
Asehnoune, K ;
Strassheim, D ;
Mitra, S ;
Kim, JY ;
Abraham, E .
JOURNAL OF IMMUNOLOGY, 2004, 172 (04) :2522-2529
[2]   The immunopathogenesis of sepsis [J].
Cohen, J .
NATURE, 2002, 420 (6917) :885-891
[3]   Neutrophils exposed to bacterial lipopolysaccharide upregulate NADPH oxidase assembly [J].
DeLeo, FR ;
Renee, J ;
McCormick, S ;
Nakamura, M ;
Apicella, M ;
Weiss, JP ;
Nauseef, WM .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (02) :455-463
[4]  
Kensler T.W., 2006, ANN REV PHARM TOXICO
[5]   Diphenyleneiodonium, an NAD(P)H oxidase inhibitor, also potently inhibits mitochondrial reactive oxygen species production [J].
Li, YB ;
Trush, MA .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1998, 253 (02) :295-299
[6]   The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling [J].
Liby, K ;
Hock, T ;
Yore, MM ;
Suh, N ;
Place, AE ;
Risingsong, R ;
Williams, CR ;
Royce, DB ;
Honda, T ;
Honda, Y ;
Gribble, GW ;
Hill-Kapturczak, N ;
Agarwal, A ;
Sporn, MB .
CANCER RESEARCH, 2005, 65 (11) :4789-4798
[7]   ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity [J].
Matsuzawa, A ;
Saegusa, K ;
Noguchi, T ;
Sadamitsu, C ;
Nishitoh, H ;
Nagai, S ;
Koyasu, S ;
Matsumoto, K ;
Takeda, K ;
Ichijo, H .
NATURE IMMUNOLOGY, 2005, 6 (06) :587-592
[8]  
Mirochnitchenko O, 1996, J IMMUNOL, V156, P1578
[9]   Endotoxemia in transgenic mice overexpressing human glutathione peroxidases [J].
Mirochnitchenko, O ;
Prokopenko, O ;
Palnitkar, U ;
Kister, I ;
Powell, WS ;
Inouye, M .
CIRCULATION RESEARCH, 2000, 87 (04) :289-295
[10]   Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts [J].
Nakahira, Kiichi ;
Kim, Hong Pyo ;
Geng, Xue Hui ;
Nakao, Atsunori ;
Wang, Xue ;
Murase, Noriko ;
Drain, Peter F. ;
Wang, Xiaomei ;
Sasidhar, Madhu ;
Nabel, Elizabeth G. ;
Takahashi, Toru ;
Lukacs, Nicholas W. ;
Ryter, Stefan W. ;
Morita, Kiyoshi ;
Choi, Augustine M. K. .
JOURNAL OF EXPERIMENTAL MEDICINE, 2006, 203 (10) :2377-2389