Cytosolic Sensors of Viral RNA Are Involved in the Production of Interleukin-6 via Toll-Like Receptor 3 Signaling in Human Glomerular Endothelial Cells

• Main Authors: Qiang Liu (Author), Tadaatsu Imaizumi (Author), Tomomi Aizawa (Author), Koji Hirono (Author), Shogo Kawaguchi (Author), Shojiro Watanabe (Author), Koji Tsugawa (Author), Tomoh Matsumiya (Author), Kazuhiko Seya (Author), Hidemi Yoshida (Author), Hiroshi Tanaka (Author)
• Format: Book
• Published: Karger Publishers, 2019-02-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1420-4096; 1423-0143; 10.1159/000498837
• Keywords: Glomerular endothelial cells; Interleukin-6; Lupus nephritis; Melanoma differentiation associated gene 5; Retinoic acid-inducible gene-I; Toll-like receptor 3; Dermatology; RL1-803; Diseases of the circulatory (Cardiovascular) system; RC666-701; Diseases of the genitourinary system. Urology; RC870-923
• Source: Kidney & Blood Pressure Research, Vol 44, Iss 1, Pp 62-71 (2019)

Background/Aims: Dysregulation of interleukin-6 (IL-6) production in residual renal cells may play a pivotal role in the development of glomerulonephritis (GN). Given that Toll-like receptor 3 (TLR3) signaling has been implicated in the pathogenesis of some forms of GN, we examined activated TLR3-mediated IL-6 signaling in cultured normal human glomerular endothelial cells (GECs). Methods: We treated GECs with polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA, and analyzed the expression of IL-6 and the cytosolic viral RNA sensors retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation associated gene 5 (MDA5) using reverse transcription quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assays. To further elucidate the effects of poly IC on this signaling pathway, we subjected the cells to small interfering RNA (siRNA) against TLR3, interferon (IFN)-β, RIG-I, and MDA5. Results: We found that poly IC induced the expression of RIG-I, MDA5 and IL-6 via TLR3/IFN-β signaling in GECs. siRNA experiments revealed that both MDA5 and RIG-I were involved in the poly IC-induced expression of IL-6, with MDA5 being upstream of RIG-I. Conclusion: Interestingly, cytosolic sensors of viral RNA were found to be involved in IL-6 production via TLR3 signaling in GECs. Regional activation of TLR3/IFN-β/ MDA5/RIG-I/IL-6 axis due to viral and "pseudoviral" infections is involved in innate immunity and inflammatory reactions in GECs. We believe this signaling pathway also plays a pivotal role in the development of some forms of GN.