Preclinical Evaluation of Targeting the Nrf2 Pathway by Triterpenoids (CDDO-Im and CDDO-Me) for Protection from LPS-Induced Inflammatory Response and Reactive Oxygen Species in Human Peripheral Blood Mononuclear Cells and Neutrophils

Thimmulappa, Rajesh K.; Fuchs, Ralph; Malhotra, Deepti; Scollick, Catherine; Traore, Kassim; Bream, Jay H.; Trush, Michael A.; Liby, Karen T.; Sporn, Michael B.; Kensler, Thomas W.; Biswal, Shyam

doi:10.1089/ars.2007.1745

Cited by 134 publications

(128 citation statements)

References 40 publications

(56 reference statements)

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“…Interestingly, it was reported that this regulation of TNF-induced VCAM-1 expression was not through NF-kB inhibition. Thimmulappa et al (9) reported that CDDO-Im (a synthetic triterpenoid) induces a number genes, including NQO1 in neutrophils, and was associated (coincided) with the inhibition of LPS-induced IL-6 and TNF induction. The results of the current study show that TNF-induced expression of NQO1 in combination with other Nrf2-regulated genes can inhibit TNF-induced TNF and IL-1b expression in human monocytes, and that this inhibition seems to be sustained and NF-kB dependent.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, the transcription factor NF-E2-related factor 2 (Nrf2) has emerged as a key regulator of inflammation (8,9). The main role of Nrf2 is to protect cells from oxidative damage by inducing the expression of various cytoprotective and detoxification genes (10).…”

mentioning

confidence: 99%

“…It also includes the regulation of glutamyl cysteine ligase modulatory (GCLM) and glutamyl cysteine ligase catalytic (GCLC) units, the two subunits of the rate-limiting enzyme in glutathione biosynthesis. Several of these Nrf2-regulated genes have been shown to have anti-inflammatory actions (8,9,(11)(12)(13)(14)(15), which suggests that Nrf2 mediates its control on inflammation by inducing the expression of any number of ARE-dependent genes.…”

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confidence: 99%

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TNF Mediates the Sustained Activation of Nrf2 in Human Monocytes

Rushworth

Shah

MacEwan

2011

The Journal of Immunology

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Modulation of monocyte function is a critical factor in the resolution of inflammatory responses. This role is mediated mainly by the production of TNF-a. Investigations of the actions of TNF have mostly focused on acute activation of other cell types such as fibroblasts and endothelial cells. Less is known about the effects of TNF on monocytes themselves, and little is known about the regulation of cell responses to TNF beyond the activation of NF-?B. In this study, we investigated the regulation of NF-E2–related factor 2 (Nrf2) cyctoprotective responses to TNF in human monocytes. We found that in monocytes TNF induces sustained Nrf2 activation and Nrf2 cytoprotective gene induction in a TNFR1-dependent manner. Under TNF activation, monocytes increased their expression of Nrf2-dependent genes, including NAD(P)H:quinone oxidoreductase 1 and glutamyl cysteine ligase modulatory, but not heme oxygenase-1. We also showed that autocrine TNF secretion was responsible for this sustained Nrf2 response and that Nrf2 activation by TNF was mediated by the generation of reactive oxygen species. Moreover, we showed that Nrf2-mediated gene induction can modulate TNF-induced NF-?B activation. These results show for the first time, to our knowledge, that TNF modulates prolonged Nrf2-induced gene expression, which in turn regulates TNF-induced inflammatory responses

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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TNF Mediates the Sustained Activation of Nrf2 in Human Monocytes

Rushworth

Shah

MacEwan

2011

The Journal of Immunology

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“…This was based on the findings that, in addition to directly binding to IKKβ, CDDO has been described to induce expression of enzymes catalyzing antioxidant reactions in peripheral blood mononuclear cells due to increased nuclear accumulation of Nrf2, an oxidant-responsive bZIP transcription factor. 40,41 Whereas EP is an effective ROS scavenger in irradiated zebrafish embryos, CDDO-TFEA did not reduce ROS levels measured 2 hours after radiation exposure ( Supplementary Fig. S5).…”

Section: The Ikk Inhibitor Cddo-tfea Mitigates Radiation Effects In Zmentioning

confidence: 95%

Nuclear Factor κB Inhibitors Alleviate and the Proteasome Inhibitor PS-341 Exacerbates Radiation Toxicity in Zebrafish Embryos

Daróczi¹,

Kari²,

Ren³

et al. 2009

TBJ

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“…ROS and peroxynitrite inhibit CD8 + T cells by catalyzing the nitration of the TCR and preventing T cell-peptide-MHC interactions essential for CD8 + activation (Wiers et al, 2000). MDSCs have thus emerged as a potential target in cancer immunotherapeutics with triterpenoids (Thimmulappa et al, 2007), arginase (Serafini et al, 2008), cyclooxygenase 2 (Sinha et al, 2007), phosphodiesterase-5 inhibitors (Serafini et al, 2006), and nitroaspirin (Nagaraj et al, 2010;Molon et al, 2011;Mundy-Bosse et al, 2011) (Mills et al, 2000). The poor antigen-presenting capability of TAMs accounts for their immune-suppressive functions.…”

Section: Role Of Myeloid-derived Suppressor Cells In Tumor Immunosuppmentioning

confidence: 99%

Failure of immunological cells to eradicate tumor and cancer cells: an overview

Sharma¹,

Talukdar²,

Malik³

et al. 2014

Turk J Biol

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Inflammation can be broadly understood as a successive immune response of an organism's immune system towards nonnative or foreign antigens. This is a protective mechanism of the immune system, mediated by diverse immunological cells, to ensure homeostasis of an individual. Once activated, these immunological cells release a number of cytokines, chemokines, reactive oxygen species, reactive nitrogen species, histamines, prostaglandins, and other materials leading to inflammation. Tumor cells express altered proteins due to mutations of their genes, DNA modifications such as histone modification, DNA methylation, or other mechanisms of altered protein expression. The body's immunological cells actively recognize these altered proteins, now acting as tumor antigens, and eliminate the tumor cell; this is popularly known as tumor immunosurveillance. However, in unmanaged or inexorable circumstances, tumor cells escape from immunosurveillance mechanisms. This ultimately leads to the cascading events of cancer development and progression. T regulatory cells, tumor-associated macrophages, and myeloid-derived suppressor cells are pronounced cells involved in immunosuppression. These cells not only dodge the immune system's surveillance but also significantly increase the survival, proliferation, and metastasis rates of tumor cells. They hinder T cytotoxic activation by secreting inhibitory cytokines (which inhibit the antitumor activity of natural killer cells) along with dendritic cells and disrupt presentation of antigens, ultimately leading to cancer development. On their own, these cells have emerged as promising therapeutic targets in cancer immunotherapy. This review highlights some of the mechanisms by which these cells escape immunosurveillance and mediate immune suppression.

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Preclinical Evaluation of Targeting the Nrf2 Pathway by Triterpenoids (CDDO-Im and CDDO-Me) for Protection from LPS-Induced Inflammatory Response and Reactive Oxygen Species in Human Peripheral Blood Mononuclear Cells and Neutrophils

Cited by 134 publications

References 40 publications

TNF Mediates the Sustained Activation of Nrf2 in Human Monocytes

TNF Mediates the Sustained Activation of Nrf2 in Human Monocytes

Nuclear Factor κB Inhibitors Alleviate and the Proteasome Inhibitor PS-341 Exacerbates Radiation Toxicity in Zebrafish Embryos

Failure of immunological cells to eradicate tumor and cancer cells: an overview

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