Synergistic Induction of Mouse Serum Amyloid A3 Promoter by the Inflammatory Mediators IL-1 and IL-6

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Abstract
Serum amyloid A (SAA), one of the major acute-phase proteins, increases several hundredfold in concentration in plasma following acute inflammation, primarily as a result of a 200-fold increase in its transcription rate. We have previously demonstrated that a 350-bp promoter fragment from the mouse SAA3 gene could confer conditioned medium-induced expression in cultured cells. The induction is mediated through a 42-bp distal response element (DRE) consisting of three functional regulatory elements. In this study, we show that interleukin-1 (IL-1) is the major cytokine in the conditioned medium responsible for SAA3 induction, and the induction by IL-1 can be effectively blocked by H-7, a protein kinase C inhibitor. Although IL-6 alone had no effect on SAA3 promoter activity, the addition of IL-6 and IL-1 resulted in dramatic synergistic activation of the reporter gene. We further show that the DRE is both necessary and sufficient to confer synergistic induction by IL-1 and IL-6. Moreover, individual mutation of the three regulatory elements within DRE either abolished or drastically reduced the synergistic induction. Our results indicate that synergistic activation of SAA3 promoter by IL-1 and IL-6 is achieved through integration of signals triggered by these two cytokines onto the DRE and that all three functionally distinct regulatory elements in the DRE are required to effectively and fully activate SAA3 gene transcription.