The cytokine IL-1beta activates IFN response factor 3 in human fetal astrocytes in culture.
The cytokine IL-1beta 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-1beta, like TLR4, signals via the MyD88/IL-1betaR-associated kinase-1 pathway linked to activation of NF-kappaB 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-beta. Using a functional genomics approach, we observed that IL-1beta induced in astrocytes a group of genes considered to be IFN-stimulated genes (ISG), suggesting that IL-1beta may also signal via IRF3 in these cells. We now show, using real-time PCR, that in astrocytes IL-1beta induces the expression of IFN-beta, IRF7, CXCL10/IFN-gamma-inducible protein-10, and CCL5/RANTES. Chemokine expression was confirmed by ELISA. We also show that IL-1beta induces phosphorylation and nuclear translocation of IRF3 and delayed phosphorylation of STAT1. The dependency of IFN-beta, IRF7, and CXCL10/IFN-gamma-inducible protein-10 gene expression on IRF3 was confirmed using a dominant negative IRF3-expressing adenovirus. The robust induction by IL-1beta 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-1beta via this pathway in human fetal astrocytes. These data are the first to show that IL-1beta, in addition to TLRs, can stimulate IRF3, implicating this cytokine as an activator of genes involved in innate antiviral responses in astrocytes.
Rivieccio
Mark A
MA
Sue Golding Graduate Division, Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. mriviecc@aecom.yu.edu
John
Gareth R
GR
Song
Xianyuan
X
Suh
Hyeon-Sook
HS
Zhao
Yongmei
Y
Lee
Sunhee C
SC
Brosnan
Celia F
CF
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects* / Q000276:immunology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005333:Fetus / Q000166:cytology / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta / Q000235:genetics; D007375:Interleukin-1 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000494:pharmacology; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016899:Interferon-beta