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Transcription Is Mediated Through the Transcription Factors Egr-1, Elk-1, and NF-
B1
*
Northwest Center for Medical Education, Indiana University School of Medicine, Gary, IN 46408; and
Departments of Pediatrics and Pathology, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90095
Bacteria and their ubiquitous cell wall component peptidoglycan
(PGN) activate the innate immune system of the host and induce the
release of inflammatory molecules. TNF-
is one of the highest
induced cytokines in macrophages stimulated with PGN; however, the
regulation of tnf- expression in PGN-activated cells
is poorly understood. This study was done to identify some of the
transcription factors that regulate the expression of the
tnf- gene in macrophages stimulated with PGN. Our
results demonstrated that PGN-induced expression of human
tnf- gene is regulated by sequences proximal to -182
bp of the promoter. Mutations within the binding sites for cAMP
response element, early growth response (Egr)-1, and 
B3
significantly reduced this induction. The transcription factor c-Jun
bound the cAMP response element site, Egr-1 bound the Egr-1 motif, and
NF-B p50 and p65 bound to the B3 site on the
tnf- promoter. PGN rapidly induced transcription of
egr-1 gene and this induction was
significantly reduced by specific mutations within the serum response
element-1 domain of the egr-1 promoter. PGN also induced
phosphorylation and activation of Elk-1, a member of the Ets family of
transcription factors. Elk-1 and serum response factor proteins bound
the serum response element-1 domain on the
egr-1 promoter, and PGN-induced
expression of the egr-1 was inhibited by
dominant-negative Elk-1. These results indicate that PGN induces
activation of the transcription factors Egr-1 and Elk-1, and that
PGN-induced expression of tnf- is directly mediated
through the transcription factors c-Jun, Egr-1, and NF-B, and
indirectly through the transcription factor
Elk-1.
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