Epstein-Barr virus-encoded small RNA induces IL-10 through RIG-I-mediated IRF-3 signaling.
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)-kappaB by dominant-negative IkappaB-alpha 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-kappaB 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-kappaB 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.
Samanta
M
M
Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Iwakiri
D
D
Takada
K
K
D002051:Burkitt Lymphoma / Q000473:pathology; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000502:physiology; D012330:RNA, Double-Stranded / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D012367:RNA, Viral / Q000235:genetics / Q000502:physiology; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
C099537:Epstein-Barr virus encoded RNA 1; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D034741:RNA, Small Interfering; D012367:RNA, Viral; D011971:Receptors, Immunologic; D016753:Interleukin-10; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases