Hepatic nuclear factor 4α positively regulates complement C3 expression and does not interfere with TNFα-mediated stimulation of C3 expression in HepG2 cells

Complement C3 is involved in various protective and regulatory mechanisms of immune system. Recently it was established that C3 expression is regulated by nuclear receptors. Hepatic nuclear factor 4 alpha. (HNF4 alpha) is a nuclear receptor critical for hepatic development and metabolism. We have shown that HNF4 alpha is a positive regulator of C3 gene expression, realizing its effects through binding to two HNF4-response elements within the C3 promoter in HepG2 cells. TNF alpha is a well established positive regulator of C3 expression in hepatocytes during acute phase of inflammation. TNF alpha decreases the amount of HNF4 alpha protein in HepG2 cells through NF-kappa B and MEK1/2 pathways thereby leading to a decrease in HNF4 alpha bound to the C3 promoter. TNF alpha and HNF4 alpha act in a synergetic way resulting in the potent activation of C3 transcription. These results suggest a novel mechanism of C3 regulation during acute phase response in HepG2 cells and display the mechanism of interaction of TNF alpha-induced pathways and HNF4 alpha in transcriptional regulation of C3 gene. (C) 2013 Elsevier B.V. All rights reserved.