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Epstein–Barr virus-encoded small RNA induces IL-10 through RIG-I-mediated IRF-3 signaling

Abstract

Epstein–Barr virus-encoded small RNA (EBER) is nonpolyadenylated, noncoding RNA, forms stem-loop structure by intermolecular base-pairing giving rise to double-stranded RNA (dsRNA)-like molecule and exists abundantly in EBV-infected cells. EBER induces IL-10 and thus supports the growth of Burkitt's lymphoma (BL) cells. In this study, the mechanism of IL-10 induction by EBER was analysed in the context of dsRNA signaling pathway. Knockdown of retinoic acid-inducible gene I (RIG-I) by small interfering RNA (siRNA), and expression of dominant-negative RIG-I downregulated IL-10 induction in EBER(+) EBV-infected and EBER plasmid-transfected BL cells. Transfection of EBER-expressing plasmid or in vitro synthesized EBER induced IL-10 in RIG-I-expressing cell clones, and activation of IL-10 promoter by EBER was blocked by dominant-negative RIG-I. Blocking of nuclear factor (NF)-κB by dominant-negative IκB-α plasmid did not block IL-10 expression, whereas knockdown of IRF-3 by siRNA resulted in downregulation of IL-10 in EBER(+) BL cells. NF-κB is reported to function downstream of RIG-I signaling pathway and is involved in the induction of proinflammatory cytokines. Our results indicate that EBER induces an anti-inflammatory cytokine IL-10 through RIG-I-mediated IRF-3 but not NF-κB signaling. These findings suggest a new mechanism of dsRNA signaling pathway that triggers the expression of IL-10, which acts as an autocrine growth factor in BL cells.

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Acknowledgements

We thank S Maruo, T Kanda and H Yoshiyama for helpful discussions and Y Ando for technical assistance. This work was supported by grants-in-aid from the Ministry of Education, Science, Sports, Culture and Technology, Japan.

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Correspondence to K Takada.

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Samanta, M., Iwakiri, D. & Takada, K. Epstein–Barr virus-encoded small RNA induces IL-10 through RIG-I-mediated IRF-3 signaling. Oncogene 27, 4150–4160 (2008). https://doi.org/10.1038/onc.2008.75

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