Peroxisome proliferator-activated receptor α positively regulates complement C3 expression but inhibits tumor necrosis factor-mediated activation of C3 gene in mammalian hepatic-derived cells

Denis A. Mogilenko, Igor V. Kudriavtsev, Vladimir S. Shavva, Ella B. Dizhe, Ekaterina G. Vilenskaya, Alexander M. Efremov, Andrej P. Perevozchikov, Sergey V. Orlov

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Background: Expression and secretion of complement C3 is positively regulated in hepatocytes during acute inflammation. Results: Activation of PPAR stimulates C3 expression but interferes with up-regulation of C3 gene by TNF-NF-B axis. Conclusion: Interplays between PPAR and TNF may be involved in control of C3 gene expression and protein secretion during acute inflammation. Significance: Novel mechanism of PPAR-dependent regulation of C3 gene in the liver has been shown. Complement C3 is a pivotal component of three cascades of complement activation. The liver is the main source of C3 in circulation and expression and secretion of C3 by hepatocytes is increased during acute inflammation. However, the mechanism of the regulation of the C3 gene in hepatocytes is not well elucidated. We showed that the C3 gene is the direct target for peroxisome proliferator-activated receptor (PPAR) in human hepatoma HepG2 cells and mouse liver. Using PPAR siRNA and synthetic PPAR agonist WY-14643 and antagonist MK886 we showed that activation ofPPAR results in up-regulation ofC3gene expression and protein secretion byHepG2cells. ThePPARresponse element (PPRE), which is able to bindPPAR in vitro and in vivo, was found in thehumanC3promoter.PPREis conservedbetweenhumanand mouse,andWY-14643stimulatesmouseC3expression in the liver. TNF increasesC3gene via NF-Band, to a lesser extent,MEK1/2 signaling pathways, whereas TNF-mediated stimulation of C3 protein secretion depends on activation of MEK1/2, p38, and JNK in HepG2 cells. Activation of PPAR abolishes TNF-mediated up-regulation of C3 gene expression and protein secretion due to interference with NF-B via PPRE-dependent mechanism in HepG2 cells. TNF decreases PPAR protein content via NF-B and MEK1/2 signaling pathways and inhibits PPAR binding with the human C3 promoter in HepG2 cells. These results suggest novel mechanism controlling C3 expression in hepatocytes during acute phase inflammation and demonstrate a crosstalk between PPAR and TNF in the regulation of complement system.

Original languageEnglish
Pages (from-to)1726-1738
Number of pages13
JournalJournal of Biological Chemistry
Volume288
Issue number3
DOIs
StatePublished - Jan 18 2013

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