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B, CCAAT/Enhancer-Binding Protein 
, and PU.1 and Identification of a Novel Repressor Element (GA-12) That Responds to IL-4 and Prostaglandin E21
*
Laboratory of Immunology, First Medical Clinic, University of Mainz, Germany; and
Cornell University, New York, NY 14853
Appropriate regulation of IL-12 expression is critical for
cell-mediated immune responses. In the present study, we have analyzed
the regulation of IL-12 p40 promoter activity in primary human
monocytes in vivo. Accordingly, we analyzed the p40 promoter by in vivo
footprinting in resting and activated primary human blood
CD14+ monocytes. Interestingly, footprints at binding sites
for trans-activating proteins such as C/EBP, NF-
B,
and ETS were only found upon stimulation with LPS and IFN-
. In
contrast, a footprint over a purine-rich sequence at -155, termed
GA-12 (GATA sequence in the IL-12 promoter), was observed in
resting, but not activated, cells. Further characterization of this
site revealed specific complex formation at a protected GATA core motif
in unstimulated primary monocytes and RAW264.7 macrophages. Mutagenesis
within the GA-12 sequence caused a significant up-regulation of
inducible IL-12 p40 promoter activity in both transient and stable
transfection systems, suggesting a repressor function of this site.
Furthermore, binding activity of the GA-12 binding protein
GAP-12 was increased by treatment with two potent inhibitors of IL-12
expression, IL-4 and PGE2. Finally, we observed that
IL-4-mediated repression of IL-12 p40 promoter activity is critically
dependent on an intact GA-12 sequence. In summary, our data underline
the complex regulation of the human IL-12 p40 promoter and identify
GA-12 as a potent, novel repressor element that mediates IL-4-dependent
suppression of inducible promoter activity in monocytes. Regulation of
GAP-12 binding may thus modulate IL-12 p40 gene
expression.
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