Regulation of the Human Acute Phase Serum Amyloid A Genes by Tumour Necrosis Factor-α, Interleukin-6 and Glucocorticoids in Hepatic and Epithelial Cell Lines

Abstract

The major acute-phase protein serum amyloid A, A-SAA, is upregulated by a variety of inflammatory stimuli, including cytokines and glucocorticoids (GCs). Elevated systemic concentrations of both A-SAA and tumour necrosis factor (TNF)-α are a feature of inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. Here, we examine the roles of TNF-α, interleukin-6 (IL-6) and GCs on the transcriptional regulation of the two human A-SAA genes (SAA1 and SAA2) and show that these stimuli have different effects on the SAA1 and SAA2 promoters in HepG2 hepatoma and KB epithelial cell lines. Both genes are induced modestly by TNF-α and IL-6 alone and synergistically by TNF-α plus IL-6. The TNF-driven induction of SAA1, but not that of SAA2, can be enhanced by GCs in both cell lines, whereas GCs alone can upregulate SAA1 only in epithelial cells. The upregulation of both genes by cytokines, and of SAA1 by GCs, is more rapid in epithelial cells than hepatoma cells. We established that the order in which either cell line was treated with TNF-α and IL-6 influenced A-SAA promoter transcriptional activation. Treatment with TNF-α followed by IL-6 resulted in a much greater induction of both A-SAA genes than treatment with IL-6 followed by TNF-α.