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Am J Nephrol. 2013;37(2):118-25. doi: 10.1159/000346415. Epub 2013 Jan 29.

Interaction between interferon-stimulated gene 56 and melanoma differentiation-associated gene 5 in Toll-like receptor 3 signaling in normal human mesangial cells.

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Department of Vascular Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.



Toll-like receptor 3 (TLR3) is a pathogen recognition receptor against viral double-stranded RNA. TLR3 signaling is important in antiviral responses, but inappropriate TLR3 signaling may be related with inflammatory renal diseases. Interferon (IFN)-stimulated gene 56 (ISG56) is an IFN-inducible gene that encodes a multifunctional protein with 6 tetratricopeptide motifs and is thought to be involved in antiviral reactions, but the role of ISG56 in TLR3 signaling in mesangial cells is not known well.


Normal human mesangial cells were cultured and treated with a synthetic TLR3 ligand polyinosinic-polycytidylic acid, and the expression of ISG56 was analyzed using real-time RT-PCR and Western blot analyses. Using an RNA-interfering technique, involvement of TLR3, IFN-β, melanoma differentiation-associated gene 5 (MDA5) or retinoic acid-inducible gene-I (RIG-I) in ISG56 expression, and of ISG56 in the expression of MDA5, RIG-I, CXCL10 and CCL5 was examined.


Treatment of cells with polyinosinic-polycytidylic acid induced ISG56. ISG56 induction was inhibited by knockdown of TLR3 or IFN-β, and knockdown of ISG56 resulted in the decreased expression of MDA5, RIG-I, CXCL10 and CCL5. RNA interference against MDA5 decreased ISG56 expression.


ISG56 was induced by TLR3 signaling via newly synthesized IFN-β. ISG56 is involved in the expression of MDA5, RIG-I, CXCL10 and CCL5, and ISG56 and MDA5 may constitute a positive-feedback loop. ISG56 may play a role in immune and inflammatory reactions induced by TLR3 signaling in human mesangial cells.

[Indexed for MEDLINE]

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