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  • Title: Differential acute-phase response of rat kininogen genes involves type I and type II interleukin-6 response elements.
    Author: Chen HM, Liao WS.
    Journal: J Biol Chem; 1993 Dec 05; 268(34):25311-9. PubMed ID: 8244962.
    Abstract:
    The serum concentration of rat T1 kininogen increases 20-30-fold in response to acute inflammation. This increase, induced in the liver, is regulated primarily at the transcriptional level. In contrast, synthesis of a homologous K kininogen is not induced. In this study, we further analyzed a 321-base pair interleukin (IL)-6 response element in the T1 kininogen promoter and showed that it consists of at least three functionally distinct sequences (A, B, and C boxes). All three sequences were required for full promoter activity. The B box, a strong C/EBP-binding site, was crucial for T1 kininogen's basal expression, whereas A and C boxes resembled the type II IL-6 response elements and were critical for the cytokine response. C/EBP alpha, -beta, and -delta interacted with the B box sequence; however, upon IL-6 stimulation, C/EBP delta binding activity was dramatically induced and became the predominant factor binding to this site. Consistent with these binding studies were the cotransfection experiments, revealing that C/EBP delta was the most potent transactivator under induced conditions and that its transactivation on the T1 kininogen promoter required an intact B box. These findings substantiated the importance of the B box in eliciting the full acute-phase response. A sequence comparison showed the K kininogen promoter contained identical A and B boxes but differed from the T1 kininogen promoter by two nucleotides at the C box. This divergence reduced the IL-6 response by approximately 4-fold, thus contributing to the differential inflammatory response. Our studies demonstrate that evolutionary divergence of a few nucleotides at a critical sequence in the promoter regions can profoundly alter the expression patterns of downstream genes.
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