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LPS-induced Expression of the Human IL-1 Receptor Antagonist Gene Is Controlled by Multiple Interacting Promoter Elements

LPS-induced Expression of the Human IL-1 Receptor Antagonist Gene Is Controlled by Multiple Interacting Promoter Elements

M F Smith Jr, D Eidlen, W P Arend, A Gutierrez-Hartmann

J Immunol. 1994 Oct 15;153(8):3584-93.

PMID: 7930581

Abstract:

Expression of the IL-1 receptor antagonist (IL-1ra) can be induced by treatment of monocytes and macrophages with LPS. We have previously demonstrated that the most proximal 294 bp of the human IL-1ra promoter are sufficient for full basal activity and LPS responsiveness. In the present study, we demonstrate the presence of one inhibitory and three positive-acting LPS response elements (LRE) within this proximal 294-bp IL-1ra promoter fragment. By both 5'-deletional analysis and heterologous promoter studies, an element between -294 and -250 was found to mask the LPS response. By 5'-deletional analysis and heterologous promoter experiments, two positive-acting LRE were identified between -250 and -200 (LRE3) and -200 and -148 (LRE2) which exhibited cooperativity in that neither element alone was active. Furthermore, LRE2 also cooperated with a more proximal site between -148 and -31 (LRE1), which also was not active alone. LRE1 was identified as an NF-kappa B-binding site. Site-directed mutagenesis of this site, located between -93 and -84, resulted in a > 50% decrease in the LPS responsiveness of the 294-bp promoter. By electrophoretic mobility shift assays, with or without specific antisera to members of the rel/NF-kappa B family, the complex binding to LRE1 was shown to contain primarily NF-kappa B1/p50 and lesser amounts of RelA/p65. These results indicate that the net activation of the human IL-1ra promoter in response to LPS involves the functional interaction of at least four cis-acting DNA elements within the proximal 294 bp.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1252362530	LRE1		1252362-53-0	Price

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