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

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 alpha (PPAR alpha) in human hepatoma HepG2 cells and mouse liver. Using PPAR alpha siRNA and synthetic PPAR alpha agonist WY-14643 and antagonist MK886 we showed that activation of PPAR alpha results in up-regulation of C3 gene expression and protein secretion by HepG2 cells. The PPAR response element (PPRE), which is able to bind PPAR alpha 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. TNF alpha increases C3 gene via NF-kappa B and, to a lesser extent, MEK1/2 signaling pathways, whereas TNF alpha-mediated stimulation of C3 protein secretion depends on activation of MEK1/2, p38, and JNK in HepG2 cells. Activation of PPAR alpha abolishes TNF alpha-mediated up-regulation of C3 gene expression and protein secretion due to interference with NF-kappa B via PPRE-dependent mechanism in HepG2 cells. TNF alpha decreases PPAR alpha protein content via NF-kappa B and MEK1/2 signaling pathways and inhibits PPAR alpha 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 alpha and TNF alpha in the regulation of complement system.