T. Kordula et al., Mechanism of interleukin-1-and tumor necrosis factor alpha-dependent regulation of the alpha(1)-antichymotrypsin gene in human astrocytes, J NEUROSC, 20(20), 2000, pp. 7510-7516
The expression of a alpha(1)-antichymotrypsin (ACT) is significantly enhanc
ed in affected brain regions in Alzheimer's disease. This serine proteinase
inhibitor specifically colocalizes with filamentous beta-amyloid deposits
and recently has been shown to influence both formation and destabilization
of beta-amyloid fibrils. In the brain, ACT is expressed in astrocytes, and
interleukin-1 (IL-1), tumor necrosis factor alpha (TNF), oncostatin M (OSM
), and IL-6/soluble IL-6 receptor complexes control synthesis of this inhib
itor. Here, we characterize a molecular mechanism responsible for both IL-1
and TNF-induced expression of ACT gene in astrocytes. We identify the 5' d
istal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream o
f the transcription start site. This 413- bp-long enhancer contains three e
lements, two of which bind nuclear factor kB (NF-kB) and one that binds act
ivating protein 1 (AP-1). All of these elements contribute to the full resp
onsiveness 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 elem
ent 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. Finall
y, we find that overexpression of the NF-kB inhibitor (IkB) totally inhibit
s any activation mediated by the newly identified IL-1/TNF enhancer of the
ACT gene.