Dendritic Cells Transduced with SOCS1 Gene Exhibit Regulatory DC Properties and Prolong Allograft Survival

SOCS1 is a key regulator of cytokine signaling and is important for maintaining balance in the immune system. It is thought to participate in negative feedback loops in cytokine signaling and may be an important signal for the regulation of dendritic cell （DC） maturation. However, it remains unclear whether DCs transduced with SOCS1 exhibit characteristics of regulatory DCs and induce allogeneic T-cell hyporesponsiveness. In this study, we constructed adenovirai vector coding SOCS1 （Ad-SOCS1） that can efficiently increase SOCS1 gene expression in bone marrow-derived dendritic cells. DCs transduced with Ad-SOCS1 （DC-SOCS1） expressed low levels of costimulatory and MHC molecules, were resistant to maturation and activation stimulation, induced allogeneic T-cell hyporesponsiveness, and promoted the generation of regulatory-like T cells in vitro. DC-SOCS1 pretreatment significantly prolonged the survival of ailografts and led to a substantial increase in the generation of regulatory T cells. Our data suggest that SOCS1 inhibits DC maturation and induces regulatory DC generation, therefore possessing therapeutic potential to prevent rejection in organ transplantation.

Hepatic Ischemia-reperfusion Injury in Mice was Alleviated by Rac1 Inhibition - More Than Just ROS-inhibition

Background and Aims:Reducing reactive oxygen species(ROS)production has proven an effective way for allevi-ating oxidative stress during ischemia-reperfusion injury(IRI).Moreover,inhibition of Rac1 could reduce ROS pro-duction and prevent oxidative stress injury.Previous stud-ies have suggested a positive interactivation feedback loop between Rac1 and hypoxia-inducible factor(HIF)-1α,the latter being up-regulated early during ischemia.The posi-tive inter-activation between Rac1 and HIF-1αwould ag-gravate ROS production,thereby promoting IRI.This study was designed to verify the effects of Rac1 inhibition on he-patic IRI both at animal and cellular levels and to explore the interaction between Rac1 and HIF-1αduring hepatic IRI.Methods:C57B/6 mice and AML-12 cells were used for the construction of hepatic IRI animal and cell models.Rac1 inhibition was achieved by NSC23766(a specific Rac1 inhibitor).Lentiviral vectors were used for Rac1 knock-down.At designated time points,serum and liver tissues were collected from the mice and treated cells were col-lected for further analysis.Results:NSC23766 treatment significantly alleviated the hepatic IRI in mice,manifesting as lower vacuolation score and less apoptosis cells,lower ROS and serum/liver alanine aminotransferase/aspartate aminotransferase levels,and fewer activated inflammatory cells.IRI of AML-12 was also alleviated by 50μM NSC23766 or Rac1-knockdown,manifesting as reduced cell apoptosis,less extensive interruption of mitochondrial membrane po-tential,down-regulation of apoptosis,and effects on DNA damage-related proteins.Interestingly,Rac1 knockdown also down-regulated the expression level of HIF-1α.Con-clusions:Our study supports a protective effect of Rac1 inhibition on hepatic IRI.Aside from the classic topics of reducing ROS production and oxidative stress,our study showed an interaction between Rac1 and HIF-1αsignaling during hepatic IRI.