Jyh. Huang et Wsl. Liao, Synergistic induction of mouse serum amyloid A3 promoter by the inflammatory mediators IL-1 and IL-6, J INTERF CY, 19(12), 1999, pp. 1403-1411
Serum amyloid A (SAA), one of the major acute-phase proteins, increases sev
eral hundredfold in concentration in plasma following acute inflammation, p
rimarily as a result of a 200-fold increase in its transcription rate. We h
ave previously demonstrated that a 350-bp promoter fragment from the mouse
SAAS gene could confer conditioned medium-induced expression in cultured ce
lls. The induction is mediated through a 42-bp distal response element (DRE
) consisting of three functional regulatory elements. In this study, we sho
w 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 effective
ly 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 i
n dramatic synergistic activation of the reporter gene. We further show tha
t the DRE is both necessary and sufficient to confer synergistic induction
by IL-1 and IL-6, Moreover, individual mutation of the three regulatory ele
ments within DRE either abolished or drastically reduced the synergistic in
duction. Our results indicate that synergistic activation of SAA3 promoter
by IL-1 and IL-6 is achieved through integration of signals triggered by th
ese two cytokines onto the DRE and that all three functionally distinct reg
ulatory elements in the DRE are required to effectively and fully activate
SAAS gene transcription.