Upregulation of ROS detoxification genes by triterpenoid CDDO-Im in macrophages: protection against lipopolysaccharide-induced inflammatory injury

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Hassan S. Ahmed (Creator)
The University of North Carolina at Greensboro (UNCG )
Web Site: http://library.uncg.edu/
Zhenquan Jia

Abstract: Dysregulated response by the body towards an infection leads to tissue and organ damage is known as sepsis. Currently, approximately 18 million people worldwide are affected by this deadly disease annually. Septic shock, a severe form of sepsis, continues to have a very high mortality rate. When the immune system fails to regulate an infection, this results in the buildup of reactive oxygen species (ROS) and cytokine storm due to an increase in pro-inflammatory cytokines. This ultimately results in organ failure and death. Currently, no viable treatment method is available to combat sepsis. Lipopolysaccharide (LPS), also known as endotoxin, is commonly used in controlled experiments to trigger the symptoms of sepsis. Macrophages, a type of immune cells, initiate a key response responsible for the cascade of events leading to the surge in inflammatory cytokines and immunopathology of septic shock. This study was undertaken to determine whether the LPS-induced inflammation could be ameliorated via the endogenous upregulation of antioxidant defense in macrophage cells. CDDO-IM (2-cyano-3,12 dioxooleana-1,9 dien-28-oyl imidazoline), a novel triterpenoid compound, was used to upregulate endogenous antioxidant defenses. Phorbol-12-myristate-13- acetate (PMA) was used to differentiate ML-1 monocytes into macrophages. This differentiation was analyzed through the increase in the expression of CD206, differentiation marker present on macrophage cells. Data from this study show that gene expression levels of inflammatory cytokine genes such as interleukin-1 beta (IL-1beta), interleukin-8 (IL-8), tumor necrosis factor-a (TNF-a) and monocyte chemoattractant protein-1 (MCP-1) were considerably increased by treatment with LPS in macrophages differentiated from ML-1 monocytes. Interestingly, LPS-induced increase in expression of pro-inflammatory cytokine levels is reduced by CDDO-IM. Additionally, CDDO-IM has been shown to protect against LPS-induced cytotoxicity in macrophages, and NF-kB transcriptional activity was also noted to decrease upon treatment with CDDO-IM in macrophages. In vivo mice trials indicated that levels of serum TNF-alpha had been significantly reduced by the administration of CDDO-IM. Also, pro-inflammatory cytokine levels of TNF-alpha, IL-6, and IL-1ß in hepatic tissue were significantly decreased as a result of CDDO-IM treatment in LPS-induced mice. This data demonstrated that the endogenous upregulation of a multitude of antioxidants by CDDO-IM attenuated LPS-induced inflammation and injury. This study may contribute to the advancement of our understanding of treating life-threatening inflammatory diseases such as sepsis. [This abstract has been edited to remove characters that will not display in this system. Please see the PDF for the full abstract.]

Additional Information

Language: English
Date: 2019
CDDO-Im, Lipopolysaccharide, ROS
Active oxygen

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