TY - JOUR
T1 - The cytokine IL-1β activates IFN response factor 3 in human fetal astrocytes in culture
AU - Rivieccio, Mark A.
AU - John, Gareth R.
AU - Song, Xianyuan
AU - Suh, Hyeon Sook
AU - Zhao, Yongmei
AU - Lee, Sunhee C.
AU - Brosnan, Celia F.
PY - 2005/3/15
Y1 - 2005/3/15
N2 - The cytokine IL-1β 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-β, like TLR4, signals via the MyD88/IL-1βR-associated kinase-1 pathway linked to activation of NF-κB 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-β. Using a functional genomics approach, we observed that IL-β induced in astrocytes a group of genes considered to be IFN-stimulated genes (ISG), suggesting that IL-1β may also signal via IRF3 in these cells. We now show, using real-time PCR, that in astrocytes IL-1β induces the expression of IFN-β, IRF7, CXCL10/IFN-γ-inducible protein-10 and CCL5/RANTES. Chemokine expression was confirmed by ELISA. We also show that IL-1β induces phosphorylation and nuclear translocation of IRF3 and delayed phosphorylation of STAT1. The dependency of IFN-β, IRF7, and CXCL10/IFN-γ-inducible protein-10 gene expression on IRF3 was confirmed using a dominant negative IRF3-expressing adenovirus. The robust induction by IL-1β 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-1β via this pathway in human fetal astrocytes. These data are the first to show that IL-1β, in addition to TLRs, can stimulate IRF3, implicating this cytokine as an activator of genes involved in innate antiviral responses in astrocytes.
AB - The cytokine IL-1β 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-β, like TLR4, signals via the MyD88/IL-1βR-associated kinase-1 pathway linked to activation of NF-κB 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-β. Using a functional genomics approach, we observed that IL-β induced in astrocytes a group of genes considered to be IFN-stimulated genes (ISG), suggesting that IL-1β may also signal via IRF3 in these cells. We now show, using real-time PCR, that in astrocytes IL-1β induces the expression of IFN-β, IRF7, CXCL10/IFN-γ-inducible protein-10 and CCL5/RANTES. Chemokine expression was confirmed by ELISA. We also show that IL-1β induces phosphorylation and nuclear translocation of IRF3 and delayed phosphorylation of STAT1. The dependency of IFN-β, IRF7, and CXCL10/IFN-γ-inducible protein-10 gene expression on IRF3 was confirmed using a dominant negative IRF3-expressing adenovirus. The robust induction by IL-1β 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-1β via this pathway in human fetal astrocytes. These data are the first to show that IL-1β, 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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U2 - 10.4049/jimmunol.174.6.3719
DO - 10.4049/jimmunol.174.6.3719
M3 - Article
C2 - 15749911
AN - SCOPUS:14844344804
SN - 0022-1767
VL - 174
SP - 3719
EP - 3726
JO - Journal of Immunology
JF - Journal of Immunology
IS - 6
ER -