Hepatic miR-301a as a Liver Transplant Rejection Biomarker? And Its Role for Interleukin-6 Production in Hepatocytes.

Acute rejection (AR) of liver transplantation remains a formidable challenge for diagnostic medicine and biomarker discovery. We characterized AR-related microRNAs (miRNAs) and the underlying AR mechanisms in liver transplantation. Using a rat model of orthotopic liver transplantation (OLT) as well as microarrays, we compared the miRNA expression profiles between naive and AR livers on day 7 after OLT with short- (<14 days, donor Dark Agouti [DA] liver into Lewis [LEW] recipient) and long-term (>60 days, donor DA liver into Piebald Virol Glaxo [PVG] recipient) survival fates. The microarray analysis revealed that the levels of miR-301a in the lethal AR livers were significantly higher than in naive and tolerogenic AR livers. The reduced expression of miR-301a in inflamed livers suggested a difference between AR and inflammation in terms of miR-301a-mediated molecular events. Overexpression of hepatic miR-301a induced IL-6 production in rat primary hepatocytes. Hepatocytes overexpressing miR-301a were capable of transferring miR-301a to cocultured splenocytes through exosomes. These splenocytes then showed overexpression of miR-301a and downregulation of protein inhibitor of activated STAT3 (PIAS3) expression, resulting in the induction of T helper 17 cell differentiation. In conclusion, this report raises the possibility that hepatic miR-301a might potentially prove value as a biomarker of liver transplant rejection. We call for future research on this molecular target and the attendant pathways as liver transplant rejection and its early diagnosis continue to be veritable healthcare challenges.