MicroRNA-122 supports robust innate immunity in hepatocytes by targeting the RTKs/STAT3 signaling pathway

MicroRNA-122 (miR-122) is the most abundant microRNA in hepatocytes and a central player in liver biology and disease. Herein, we report a previously unknown role for miR-122 in hepatocyte intrinsic innate immunity. Restoring miR-122 levels in hepatoma cells markedly enhanced the activation of interferons (IFNs) in response to a variety of viral nucleic acids or simulations, especially of hepatitis C virus RNA and poly (I:C). Mechanistically, miR-122 down-regulated the phosphorylation (Tyr705) of STAT3 and thereby removed the negative regulation of STAT3 on IFN-signaling. While STAT3 represses IFN expression by inhibiting interferon regulatory factor 1 (IRF1); miR-122 targets MERTK, FGFR1 and IGF1R, three receptor tyrosine kinases (RTKs) that directly promote STAT3 phosphorylation. This work identifies a miR-122–RTKs/STAT3–IRF1–IFNs regulatory circuitry, which may play a pivotal role in regulating hepatocyte innate immunity. These findings renewed our knowledge about miR-122’s function and have important implications for treating hepatitis viruses. We used microarrays to analyze which genes were down-regulated by miR-122. In order to accurately obtain the gene pools down-regulated by miR-122, we employed both transient and stable miR-122 over-expression in HepG2 cells. Transient over-expression was performed by transfection of miR-122 mimics. For stable over-expression of miR-122, we generated a miR-122-Tet-On HepG2 cell line in which the miR-122 is under the control of an inducible promoter. Adding doxycycline to the culture medium induced high level of miR-122 expression. RNAs were sent to microarray analysis with GeneChip® Human Genome U133 Plus 2.0 Arrays.