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Activates IFN Response Factor 3 in Human Fetal Astrocytes in Culture 1
,
* Sue Golding Graduate Division, Departments of
Pathology and
Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461; and
Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029
The cytokine IL-1
is a major activator of primary human fetal astrocytes in culture, leading to the production of a wide range of cytokines and chemokines important in the host defense against pathogens. IL-1, like TLR4, signals via the MyD88/IL-1R-associated kinase-1 pathway linked to activation of NF-
B and AP-1. Recent studies have shown that TLR4 also signals independently of MyD88, resulting in the activation of IFN regulatory factor 3 (IRF3), a transcription factor required for the production of primary antiviral response genes such as IFN-. Using a functional genomics approach, we observed that IL-1 induced in astrocytes a group of genes considered to be IFN-stimulated genes (ISG), suggesting that IL-1 may also signal via IRF3 in these cells. We now show, using real-time PCR, that in astrocytes IL-1 induces the expression of IFN-, IRF7, CXCL10/IFN-
-inducible protein-10, and CCL5/RANTES. Chemokine expression was confirmed by ELISA. We also show that IL-1 induces phosphorylation and nuclear translocation of IRF3 and delayed phosphorylation of STAT1. The dependency of IFN-, IRF7, and CXCL10/IFN--inducible protein-10 gene expression on IRF3 was confirmed using a dominant negative IRF3-expressing adenovirus. The robust induction by IL-1 of additional ISG noted on the microarrays, such as STAT1, 2'5'-oligoadenylate synthetase 2, and ISG15, also supports an active signaling role for IL-1 via this pathway in human fetal astrocytes. These data are the first to show that IL-1, in addition to TLRs, can stimulate IRF3, implicating this cytokine as an activator of genes involved in innate antiviral responses in astrocytes.
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