Suppression of histone deacetylase 11 promotes expression of IL-10 in Kupffer cells and induces tolerance following orthotopic liver transplantation in rats.

Background: Suppression of histone deacetylase 11 (HDAC11) can promote IL-10 expression in mouse macrophages RAW264.7 and induce immune tolerance. This study is to further investigate the role of HDAC11 in tolerance induction via Kupffer cells (KCs) following orthotopic liver transplantation (OLT) in rats.

Materials And Methods: 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 [(3)H]-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.

Results: 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-α, and IFN-γ 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.

Conclusions: 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.