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Gene Promoter by IL-1 in Monocytes
*
First Department of Internal Medicine, School of Medicine, and
School of Health Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan;
Department of Legal Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan; and
Department of Medicine, New England Baptist Bone and Joint Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02181
IL-1
is produced primarily by activated monocytes/macrophages.
We report in this study that IL-1 induces the human pro-IL-1
(IL1B) gene promoter in human THP-1 monocytic
cells. The -131 to +12 minimal IL1B promoter was induced by IL-1 in
a dose-dependent manner. The promoter possesses two important
transcription factor binding motifs, one for an ETS family
transcription factor Spi-1 (PU.1), and the other a binding site for
NF-IL6 (CCAAT/enhancer binding protein ). Autocrine promoter
activity was completely inhibited by mutation of the Spi-1 site.
Mutation of the NF-IL6 binding motif caused partial loss of activity.
EMSAs using THP-1 cell nuclear extracts indicated that IL-1
significantly induced Spi-1 binding to its target site within the IL1B
promoter that was maximal at 1 h after stimulation, correlating
with the kinetics of IL-1 induction. The importance of Spi-1 was
supported by our observation that Spi-1-deficient EL4 thymocytes
exhibited IL-1-induced activity only after transfection with a Spi-1
expression vector. Moreover, TNFR-associated factor 6 also required
Spi-1 to activate the promoter. Transfection studies using Spi-1 mutant
constructs showed that the TATA-binding protein binding and
glutamine-rich domains of Spi-1 were important for IL-1 induction,
whereas LPS induction required the proline, glutamic acid, serine, and
threonine-rich domain containing serine 148 as well as the
TATA-binding protein and glutamine-rich domains. We conclude that the
IL1B promoter is an IL-1-responsive sequence as a result
of its ability to bind Spi-1 in response to
IL-1.
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