KCs isolated from BALB/c mice were divided into pHDAC11, adHDAC11, and pCV group (treated with HADC11-shRNA, adenovirus encoding HDAC11, and control vector, respectively). IL-10 expression was determined after lipopolysaccharide treatment. The expression of MHC-II and co-stimulatory molecules on KCs surface was evaluated by flow cytometry. T cell proliferation was measured by [3H]-thymidine incorporation after culturing with aforementioned three groups, treated KCs, respectively. OLT was performed in rats after Ad-HDAC11 and pHDAC11 treatment. Blood samples were collected for biochemical studies, and postoperative survival was examined.
IL-10 expression was inhibited and promoted by Ad-HDAC11 and HDAC11-shRNA in KCs, respectively. MHC-II and co-stimulatory molecules on KCs surface as well as T cell proliferation were significantly inhibited and induced in pHDAC11 and Ad-HDAC11 compared with pCV, respectively. Serum IL-2, TNF-伪, and IFN-纬 levels were significantly lower in pHDAC11 and higher in Ad-HDAC11 compared with pCV, respectively, while IL-4 and IL-10 were the reverse. Postoperative survival, liver function, and histology were different among the three groups.
Suppression of HDAC11 can promote IL-10 expression in KCs and induce tolerance following OLT in rats. Consequently, HDAC11 may be a key component of this immune regulation system and a promising target for development of novel drugs of gene therapy for inducing tolerance in clinical liver transplantation.
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