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The Journal of Neuroscience, October 15, 2000, 20(20):7510-7516

Mechanism of Interleukin-1- and Tumor Necrosis Factor -Dependent Regulation of the ₁-Antichymotrypsin Gene in Human Astrocytes

Tomasz Kordula¹, Marcin Bugno¹, Russell E. Rydel², and James Travis³

¹ Institute of Molecular Biology, Jagiellonian University, 31-120 Kraków, Poland, ² Elan Pharmaceuticals, South San Francisco, California 94080, and ³ Department of Biochemistry and Molecular Biology, The University of Georgia, Athens, Georgia 30602

The expression of ₁-antichymotrypsin (ACT) is significantly enhanced in affected brain regions in Alzheimer's disease. This serine proteinase inhibitor specifically colocalizes with filamentous -amyloid deposits and recently has been shown to influence both formation and destabilization of -amyloid fibrils. In the brain, ACT is expressed in astrocytes, and interleukin-1 (IL-1), tumor necrosis factor  (TNF), oncostatin M (OSM), and IL-6/soluble IL-6 receptor complexes control synthesis of this inhibitor. Here, we characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. In addition, we demonstrate that the 5' untranslated region of the ACT mRNA does not contribute to cytokine-mediated activation. Finally, we find that overexpression of the NF-kB inhibitor (IkB) totally inhibits any activation mediated by the newly identified IL-1/TNF enhancer of the ACT gene.

Key words: ₁-antichymotrypsin; Alzheimer's disease; IL-1; TNF; regulation; transcription; enhancer; NF-kB; AP-1

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20207510-07$05.00/0

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