Inhibition of histone deacetylase 11 (HDAC11) promotes IL-10 expression in mouse macrophages RAW264.7 and induces immune tolerance. Here, researchers investigated the role of HDAC11 in the induction of immune tolerance in Kupffer cells (KCs) after orthotopic liver transplantation (OLT) in rats. KCs isolated from BALB/c mice were divided into pHDAC11, adHDAC11, and pCV groups (treated with HADC11-shRNA, adenovirus encoding HDAC11, and control vector, respectively). After Ad-HDAC11 and pHDAC11 treatment, rats were subjected to OLT. In KCs, Ad-HDAC11 and HDAC11-shRNA inhibited and promoted IL-10 expression, respectively. Compared with the pCV group, MHC-II class molecules and co-stimulatory molecules on the surface of KCs and T cell proliferation were significantly inhibited and induced in the pHDAC11 and Ad-HDAC11 groups. Compared with the pCV group, the serum levels of IL-2, TNF-α, and IFN-γ in the pHDAC11 group were significantly decreased, while the serum levels of IL-4 and IL-10 in the Ad-HDAC11 group were significantly increased. These results suggest that inhibition of HDAC11 can promote the expression of IL-10 in KCs after rat liver transplantation and induce hepatocyte tolerance. Therefore, HDAC11 may be a key component of this immune regulatory system and a promising target for the development of new gene therapy drugs to induce tolerance in clinical liver transplantation.
Recipients were sacrificed to evaluate histologic changes at indicated time points. Light microscopy showed that the transplanted kidneys of rats in the Ad-HDAC11 group underwent acute rejection, while the rejection in the pHDAC11 group was mild (Figure 1). ALT (U/L) and TBIL (mmol/L) of rats in the Ad-HDAC11 group increased significantly, and ALB (g/L) decreased, indicating severe liver damage. However, the above liver function indicators of rats in the pHDAC11 group changed slightly, indicating that the liver damage of rats in the pHDAC11 pretreatment group was mild.
Figure 1. Pathologic alterations of each group at 3 d after OLT, light microscopy (LM) hematoxylin-eosin (HE) X400. (Lian Z, et al., 2012)
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