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Reporters in Nontransformed T Cells1
*
Department of Pathology and Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110;
Department of Pathology, University of Alabama, Birmingham, AL 35294
Analysis of the IFN-
promoter has primarily been conducted by
transient expression of reporter constructs in transformed cells.
However, the activity of cis elements may differ when
expressed transiently compared with their activity within native
chromatin. Furthermore, the transcription factors and signaling
mechanisms in transformed cells may differ from those in normal T
cells. To analyze IFN- promoter regulation in normal T cells, we
developed a novel retroviral bottom-strand reporter system to allow the
chromatin integration of promoter regions in primary developing T
cells. As controls, both the IL-2 and IL-4 promoters were inducible in
this system, with the IL-4 reporter having Th2-specific activity.
Strikingly, the IFN- promoter exhibited constitutive activity in
both Th1 and Th2 subsets, in contrast to the behavior of the endogenous
IFN- gene, which is inducible only in Th1 cells. In mapping this
activity, we found that the AP-1/GM-CSF site in the distal promoter
element is the most critical element for the constitutive activity.
Transgenic reporter lines for the IFN- promoter confirmed the
constitutive behavior of the isolated IFN- promoter. This
constitutive activity was resistant to inhibition by cyclosporin A and
was independent of Stat4 and p38 mitogen-activated protein kinase.
These results suggest that IFN- promoter regulation may require
cis elements residing either downstream or >3.4 kb
upstream of the transcriptional start site, involving repression of
constitutive activity.
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