Abstract
Spontaneous immune tolerance in mouse liver transplantation has always been a hotspot in transplantation-immune research. Recent studies revealed that regulatory T cells (Tregs), hepatic satellite cells and Kupffer cells play a potential role in spontaneous immune tolerance, however the precise mechanism of spontaneous immune tolerance is still undefined. By using Microarray Chips, we investigated different immune regulatory factors to decipher critical mechanisms of spontaneous tolerance after mouse liver transplantation. Allogeneic (C57BL/6-C3H) and syngeneic (C3H-C3H) liver transplantation were performed by 6-8 weeks old male C57BL/6 and C3H mice. Graft samples (N = 4 each group) were collected from 8 weeks post-operation mice. 11 differentially expressed miRNAs in allogeneic grafts (Allografts) vs. syngeneic grafts (Syngrafts) were identified using Agilent Mouse miRNA Chips. It was revealed that 185 genes were modified by the 11 miRNAs, furthermore, within the 185 target genes, 11 of them were tightly correlated with immune regulation after Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Genbank data cross-comparison. Verified by real-time PCR and western blot, our results indicated that mRNA expression levels of IL-6 and TAB2 were respectively down regulated following miR-142-3p and miR-155 augment. In addition, increased miR-152 just silenced mRNA of CaMK II and down-regulated translation of CaMK II in tolerated liver grafts, which may play a critical role in immune regulation and spontaneous tolerance induction of mouse liver transplantation.
Highlights
Liver transplantation is an established therapeutic option for acute and chronic end-stage liver diseases, metabolic diseases and early hepatocellular carcinoma [1]
Orthotropic liver transplantation and Sample Collection C57BL/6 or C3H mice weighing 23,25g were used as donors and C3H mice weighing 24,26 g were used as recipients for allogeneic or syngeneic liver transplantation, respectively
Different miRNAs expressed in allografts/ syngrafts, normal liver of C57BL/6 and C3H mice were shown in Figure 1A. 11 different miRNAs from liver transplantation grafts were identified (Table 2), while 26 miRNAs were expressed differently in normal C57BL/6 and C3H mouse liver (Table 3)
Summary
Liver transplantation is an established therapeutic option for acute and chronic end-stage liver diseases, metabolic diseases and early hepatocellular carcinoma [1]. Donor shortage and side effects of immunosuppressants are the two major issues that hamper the progress of liver transplantation. Immunosuppressant is still needed for recipients, the side effects and complications such as infection and tumor recurrence have always been the vexing challenges for clinical physicians [3]. The ability to produce a tolerant state after transplantation would potentially obviate long-term immunosuppressant usage. Researches have been done to demonstrate the mechanisms of graft dysfunction and immune tolerance. Ye Y. and colleagues provided new evidence of the potential regulatory effects of galectin-1 in allogeneic immune responses in a murine model of liver transplantation [5]. The exact mechanisms involved in the complicated immune system to achieve tolerance remain unclear, and the results of clinical operational tolerance are still unpersuasive
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