J. Biol. Chem., Vol. 268, Issue 34, 25311-25319, Dec, 1993
Differential acute-phase response of rat kininogen genes involves type I and type II interleukin-6 response elements
HM Chen and WS Liao
Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
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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