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4-Octyl Itaconate Activates Nrf2 Signaling To Inhibit Pro-Inflammatory Cytokine Production In Peripheral Blood Mononuclear Cells Of Systemic Lupus Erythematosus Patients

Chunrong Tang, Xiaohua Wang, Yingying Xie, X. Cai, Na Yu, Yudan Hu, Zhihua Zheng
Published 2018 · Medicine, Chemistry

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Background/Aims: Increased production of multiple pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, plays an essential pathogenic role in the progression of systemic lupus erythematosus (SLE). Recent studies have characterized itaconate as a novel and potent nuclear-factor-E2-related factor 2 (Nrf2) activator that activates Nrf2 signaling by alkylating cysteine residues on Keap1 (Kelch-like ECH-associated protein 1). Methods: THP-1 human macrophages and peripheral blood mononuclear cells (PBMCs) of SLE patients were treated with 4-octyl itaconate (OI). Nrf2 signaling activation was tested by qPCR assay and western blotting. mRNA expression and the production of multiple pro-inflammatory cytokines were tested by qPCR and enzyme-linked immunosorbent assays, respectively. Nuclear factor (NF)-κB activation was tested by the p65 DNA-binding assay. Results: We demonstrated that OI, the cell-permeable derivative of itaconate, induced Keap1-Nrf2 dissociation, Nrf2 protein accumulation, and nuclear translocation, which enabled the transcription and expression of multiple Nrf2-dependentantioxidant enzymes (heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, and glutamate-cysteine ligase modifier subunit) in THP-1 human macrophages. OI also induced significant Nrf2 activation in SLE patient-derived PBMCs. OI pretreatment inhibited mRNA expression and the production of multiple pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in SLE patient-derived PBMCs and lipopolysaccharide (LPS)-activated THP-1 cells. OI potently inhibited NF-κB activation in SLE patient-derived PBMCs and LPS-activated THP-1 cells. Importantly, Nrf2 silencing (by targeted short hairpin RNA) or knockout (by CRISPR/Cas9 gene-editing method) almost abolished OI-induced anti-oxidant and anti-inflammatory actions in SLE patient-derived PBMCs and LPS-activated THP-1 cells. Conclusion: OI activates Nrf2 signaling to inhibit the production of pro-inflammatory cytokines in human macrophages and SLE patient-derived PBMCs. OI and itaconate could have important therapeutic value for the treatment of SLE.
This paper references
A. Gunn (1943)
Detection of measles virus-induced apoptosis of human monocytic cell line (THP-1) by DNA fragmentation ELISA.
M. Ito (1996)
Renal expression of IL-6 and TNFalpha genes in lupus nephritis.
R. Herrera-Esparza (1998)
Renal expression of IL-6 and TNFα genes in lupus nephritis
R Herrera-Esparza (1998)
A possible role of oxidative stress in the vanadium-induced cytotoxicity in the MC3T3E1 osteoblast and UMR106 osteosarcoma cell lines.
A. Cortizo (2000)
Nrf2-deficient female mice develop lupus-like autoimmune nephritis.
K. Yoh (2001)
Lipopolysaccharide induces Rac1-dependent reactive oxygen species formation and coordinates tumor necrosis factor-alpha secretion through IKK regulation of NF-kappa B.
S. Sanlioglu (2001)
Lipopolysaccharide Induces Rac1-dependent Reactive Oxygen Species Formation and Coordinates Tumor Necrosis Factor-α Secretion through IKK Regulation of NF-κB*
S. Sanlioglu (2001)
Cutting Edge: Direct Interaction of TLR4 with NAD(P)H Oxidase 4 Isozyme Is Essential for Lipopolysaccharide-Induced Production of Reactive Oxygen Species and Activation of NF-κB1
H. Park (2004)
Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles.
K. Itoh (2004)
Preliminary results of safety and efficacy of the interleukin 1 receptor antagonist anakinra in patients with severe lupus arthritis
B. Ostendorf (2004)
Molecular mechanisms of Nrf2‐mediated antioxidant response
Wenge Li (2009)
Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study.
G. Illei (2010)
Transcription profiles of LPS-stimulated THP-1 monocytes and macrophages: a tool to study inflammation modulating effects of food-derived compounds.
W. Chanput (2010)
Nrf2-Keap1 Signaling as a Potential Target for Chemoprevention of Inflammation-Associated Carcinogenesis
J. Kundu (2010)
Novel biological treatments for systemic lupus erythematosus: current and future modalities.
S. Bezalel (2012)
Immunopathological Roles of Cytokines, Chemokines, Signaling Molecules, and Pattern-Recognition Receptors in Systemic Lupus Erythematosus
Shui-Lian Yu (2012)
Therapeutic blockade of TNF in patients with SLE-promising or crazy?
M. Aringer (2012)
Roles of Pro- and Anti-Inflammatory Cytokines in the Pathogenesis of SLE
D. Su (2012)
IL-37 inhibits the production of inflammatory cytokines in peripheral blood mononuclear cells of patients with systemic lupus erythematosus: its correlation with disease activity
Liang Ye (2014)
Nrf2 suppresses lupus nephritis through inhibition of oxidative injury and the NF-κB-mediated inflammatory response
T. Jiang (2013)
K6PC-5, a novel sphingosine kinase 1 (SphK1) activator, alleviates dexamethasone-induced damages to osteoblasts through activating SphK1-Akt signaling.
F. Ji (2015)
Molecular basis of the Keap1-Nrf2 system.
T. Suzuki (2015)
Trametinib, a novel MEK kinase inhibitor, suppresses lipopolysaccharide-induced tumor necrosis factor (TNF)-α production and endotoxin shock.
Du Shi-lin (2015)
Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways
J. D. Wardyn (2015)
Oxidative stress response and Nrf2 signaling in aging.
H. Zhang (2015)
Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis
C. Mohan (2015)
Prevention of glucocorticoid induced-apoptosis of osteoblasts and osteocytes by protecting against endoplasmic reticulum (ER) stress in vitro and in vivo in female mice.
Amy Y. Sato (2014)
Palmitate-Induced MMP-9 Expression in the Human Monocytic Cells is Mediated through the TLR4-MyD88 Dependent Mechanism
S. Sindhu (2016)
miR-135b-5p inhibits LPS-induced TNFα production via silencing AMPK phosphatase Ppm1e
P. Li (2016)
New insights into the immunopathogenesis of systemic lupus erythematosus
G. Tsokos (2016)
Inhibition of EMMPRIN and MMP-9 Expression by Epigallocatechin-3-Gallate through 67-kDa Laminin Receptor in PMA-Induced Macrophages
Q. Wang (2016)
KE: New insights into the immunopathogenesis of systemic lupus erythematosus
GC Tsokos (2016)
miR - 135 b - 5 p inhibits LPS - induced TNFalpha production via silencing AMPK phosphatase Ppm 1 e
P Li (2016)
Antioxidant and Hepatoprotective Effect of Swertiamarin on Carbon Tetrachloride-Induced Hepatotoxicity via the Nrf2/HO-1 Pathway
T. Wu (2017)
GSK1059615 kills head and neck squamous cell carcinoma cells possibly via activating mitochondrial programmed necrosis pathway.
J. Xie (2017)
Immunometabolism in systemic lupus erythematosus
L. Morel (2017)
MIND4-17 protects retinal pigment epithelium cells and retinal ganglion cells from UV
C. Li (2017)
Ginseng Rh2 protects endometrial cells from oxygen glucose deprivation/re-oxygenation
X. Tang (2017)
Microarray Expression Profile of Circular RNAs in Peripheral Blood Mononuclear Cells from Rheumatoid Arthritis Patients
Q. Ouyang (2017)
Antioxidant and Hepatoprotective Effect of Swertiamarin on Carbon TetrachlorideInduced Hepatotoxicity via the Nrf2/HO-1 Pathway
T Wu (2017)
Activation of KGFR-Akt-mTOR-Nrf2 signaling protects human retinal pigment epithelium cells from Ultra-violet.
Haitao Hu (2018)
Keratinocyte growth factor protects endometrial cells from oxygen glucose deprivation/re-oxygenation via activating Nrf2 signaling.
Xuting Shi (2018)
Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1
E. Mills (2018)

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X. Teng (2020)
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Ankit Tandon (2020)
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Altered redox regulation by Nrf2-Keap1 system in dendritic cells of systemic lupus erythematosus patients
Preeti Gautam (2020)
Activation of Keap1-Nrf2 signaling by 4-octyl itaconate protects human umbilical vein endothelial cells from high glucose.
Chunrong Tang (2019)
Protective effects of dimethyl itaconate in mice acute cardiotoxicity induced by doxorubicin.
Qing Shan (2019)
Immunometabolism in Rheumatic Disease : The Role in Pathogenesis and Implications for Treatment
C. Wincup (2019)
Crystal structure of cis-aconitate decarboxylase reveals the impact of naturally occurring human mutations on itaconate synthesis
F. Chen (2019)
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