Abstract
Although the mechanisms that regulate CYP4F genes have been and are currently being studied in a number of laboratories, the specific mechanisms for the regulation of these genes are not yet fully understood. This study shows that nuclear factor κB of the light-chain-enhancer in activated B cells (NF-κB) can inhibit CYP4F11 expression in human liver carcinoma cell line (HepG2) as summarized below. Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, has been shown to activate NF-κB signaling while also activating the c-Jun NH2-terminal kinase (JNK) signaling pathway. Other studies have reported that JNK signaling can up-regulate CYP4F11 expression. The results of this study demonstrate that in the presence of TNF-α and the specific NF-κB translocation inhibitor N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (IMD-0354), there is a greater increase in CYP4F11 expression than that elicited by TNF-α alone, indicating that NF-κB plays an inhibitory role. Moreover, NF-κB stimulation by overexpression of mitogen-activated protein kinase kinase kinase inhibited CYP4F11 promoter expression. CYP4F11 promoter inhibition can also be rescued in the presence of TNF-α when p65, a NF-κB protein, is knocked down. Thus, NF-κB signaling pathways negatively regulate the CYP4F11 gene.
Footnotes
This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS44174]; the National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases [Grant AR45603]; and the National Institutes of Health National Institute of General Medical Sciences [Grant 1F31-GM081907-01].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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ABBREVIATIONS:
- TNF-α
- tumor necrosis factor-α
- IL
- interleukin
- P450
- cytochrome P450
- AP-1
- activator protein 1
- IMD-0354
- N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
- PBS
- phosphate-buffered saline
- PCR
- polymerase chain reaction
- ChIP
- chromatic immunoprecipitation
- bp
- base pair
- kb
- kilobase
- siRNA
- small interfering RNA
- NF-κB
- nuclear factor κB of the light-chain-enhancer in activated B cells
- JNK
- c-Jun NH2-terminal kinase
- MEKK
- mitogen-activated protein kinase kinase kinase.
- Received June 28, 2011.
- Accepted October 19, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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