ISG54 and ISG56 are induced by TLR3 signaling in U373MG human astrocytoma cells: possible involvement in CXCL10 expression.

Toll-like receptor (TLR) 3 is a pattern recognition receptor that recognizes double-stranded RNA (dsRNA). TLR3 signaling in astrocytes leads to the expression of interferon-ß (IFN-ß), and IFN-ß regulates immune and inflammatory reactions by inducing IFN-stimulated genes (ISGs). We demonstrated in the present study that polyinosinic-polycytidylic acid (poly IC), an authentic dsRNA, up-regulated the expression of ISG54 and ISG56 in U373MG human astrocytoma cells. This reaction was confirmed to be mediated via the TLR3/IFN-ß pathway. We also found that ISG56 positively regulates the expression of ISG54, retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). In addition, positive feedback loops were found between ISG54 and ISG56, and also between ISG54 and RIG-I. RNA interference experiments revealed that all of ISG54, ISG56, RIG-I and MDA5 were involved in the poly IC-induced expression of a chemokine CXCL10. These results suggest that ISG54 and ISG56 are involved in the induction of CXCL10 in TLR3/IFN-ß signaling at least partly by co-operating with RIG-I and MDA5. ISG54 and ISG56 may contribute to immune and inflammatory reactions elicited by the TLR3/IFN-ß signaling pathway in astrocytes, and may play an important role both in antiviral immunity and in neuroinflammatory diseases.