Dihydro-CDDO-trifluoroethyl amide suppresses inflammatory responses in macrophages via activation of Nrf2.
Nuclear factor erythroid 2-related factor (Nrf2) is the major regulator of cellular defenses against various pathological stresses in a variety of organ systems, thus Nrf2 has evolved to be an attractive drug target for the treatment and/or prevention of human disease. Several synthetic oleanolic triterpenoids including dihydro-CDDO-trifluoroethyl amide (dh404) appear to be potent activators of Nrf2 and exhibit chemopreventive promises in multiple disease models. While the pharmacological efficacy of Nrf2 activators may be dependent on the nature of Nrf2 activation in specific cell types of target organs, the precise role of Nrf2 in mediating biological effects of Nrf2 activating compounds in various cell types remains to be further explored. Herein we report a unique and Nrf2-dependent anti-inflammatory profile of dh404 in inflamed macrophages. In lipopolysaccharide (LPS)-inflamed RAW264.7 macrophages, dh404 dramatically suppressed the expression of pro-inflammatory cytokines including inducible nitric oxide synthase (iNOS), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1 beta (MIP-1β), while minimally regulating the expression of interleulin-6 (IL-6), IL-1β, and tumor necrosis factor alpha (TNFα). Dh404 potently activated Nrf2 signaling; however, it did not affect LPS-induced NF-κB activity. Dh404 did not interrupt the interaction of Nrf2 with its endogenous inhibitor Kelch-like ECH associating protein 1 (Keap1) in macrophages. Moreover, knockout of Nrf2 blocked the dh404-induced anti-inflammatory responses in LPS-inflamed macrophages. These results demonstrated that dh404 suppresses pro-inflammatory responses in macrophages via an activation of Nrf2 independently of Keap1 and NF-κB, suggesting a unique therapeutic potential of dh404 for specific targeting a Nrf2-mediated resolution of inflammation.
Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
Bin
B
Li
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
Akram
A
Abdalrahman
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
Yimu
Y
Lai
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
Joseph S
JS
Janicki
Department of Pharmacology, Reata Pharmaceuticals, Inc., Irving, TX 75063, USA.
Keith W
KW
Ward
Department of Pharmacology, Reata Pharmaceuticals, Inc., Irving, TX 75063, USA.
Colin J
CJ
Meyer
Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China.
Xing Li
XL
Wang
Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA. Electronic address: Dongqi.Tang@uscmed.sc.edu.
Dongqi
D
Tang
Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA. Electronic address: taixing.cui@uscmed.sc.edu.
Taixing
T
Cui
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000276:immunology; D054407:Chemokine CCL4 / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000276:immunology; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; C491768:Ccl2 protein, mouse; C496535:Ccl4 protein, mouse; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D016207:Cytokines; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; C547749:dh404 compound; D009828:Oleanolic Acid; D052247:Nitric Oxide Synthase Type II
Dh404; Inflammation; Macrophages; Nrf2