title: Peroxisome proliferator-activated receptor α positively regulates complement C3 expression but inhibits tumor necrosis factor α-mediated activation of C3 gene in mammalian hepatic-derived cells.
abstract: 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 α (PPARα) in human hepatoma HepG2 cells and mouse liver. Using PPARα siRNA and synthetic PPARα agonist WY-14643 and antagonist MK886 we showed that activation of PPARα results in up-regulation of C3 gene expression and protein secretion by HepG2 cells. The PPAR response element (PPRE), which is able to bind PPARα in vitro and in vivo, was found in the human C3 promoter. PPRE is conserved between human and mouse, and WY-14643 stimulates mouse C3 expression in the liver. TNFα increases C3 gene via NF-κB and, to a lesser extent, MEK1/2 signaling pathways, whereas TNFα-mediated stimulation of C3 protein secretion depends on activation of MEK1/2, p38, and JNK in HepG2 cells. Activation of PPARα abolishes TNFα-mediated up-regulation of C3 gene expression and protein secretion due to interference with NF-κB via PPRE-dependent mechanism in HepG2 cells. TNFα decreases PPARα protein content via NF-κB and MEK1/2 signaling pathways and inhibits PPARα 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 PPARα and TNFα in the regulation of complement system.
authors.affiliation: Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, St. Petersburg 197376, Russia. denis@iem.sp.ru
authors.forename: Denis A
authors.initials: DA
authors.lastname: Mogilenko
authors.forename: Igor V
authors.initials: IV
authors.lastname: Kudriavtsev
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Shavva
authors.forename: Ella B
authors.initials: EB
authors.lastname: Dizhe
authors.forename: Ekaterina G
authors.initials: EG
authors.lastname: Vilenskaya
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Efremov
authors.forename: Andrej P
authors.initials: AP
authors.lastname: Perevozchikov
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Orlov
mesh_terms: D000818:Animals; D003176:Complement C3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics* / Q000276:immunology; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011485:Protein Binding; D011743:Pyrimidines / Q000494:pharmacology; D020218:Response Elements; D015398:Signal Transduction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D003176:Complement C3; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; C006253:pirinixic acid; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482129:Map2k2 protein, mouse