Shaohua Song

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 adenoviral 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 allografts 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.

Protective role of autophagy in methionine–choline deficient diet-induced advanced nonalcoholic steatohepatitis in mice ☆

The methionine choline-deficient (MCD) diet leads to severe liver injury similar to human nonalcoholic steatohepatitis (NASH). Autophagy has emerged as a critical lysosomal pathway that maintains cell function and survival through the degradation of cellular components such as organelles and proteins. The goal of this study was to elucidate the role of autophagy in MCD-induced steatosis, fibrosis, inflammation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in mice. Mice were fed with MCD diet and treated with rapamycin (an autophagy enhancer) or chloroquine (an autophagy inhibitor) for 10 weeks. Liver injury was evaluated biochemically and histologically together with hepatic gene expression analysis. Autophagic flux was impaired in livers of mice fed with MCD diet, evidenced by reduced ratio of LC3-II/LC3-I and increased protein expression of p62. It was found that autophagy activation by rapamycin attenuated MCD-induced steatosis, fibrosis, inflammation, mitochondrial dysfunction, and ER stress. By contrast, MCD mice treated with chloroquine developed more liver injury. In conclusions, the autophagic pathway plays an important protective role in MCD-induced advanced NASH. Thus, pharmacological promotion of autophagy may provide a novel therapeutic strategy for treatment of NASH.

Sinomenine pretreatment attenuates cold ischemia/reperfusion injury in rats: The role of heme oxygenase-1

Ischemia/reperfusion (I/R) injury can be characterized as an inflammatory response including recruitment of inflammatory cells to a post-ischemic organ or tissue and a cascade of mediators. Sinomenine (SIN), a pure alkaloid extracted from the Chinese medical plant Sinomenium acutum, has been used to treat various inflammatory diseases including rheumatism and arthritis. However, whether SIN can attenuate I/R injury has not previously been examined. Using a syngeneic orthotopic liver transplantation model in rats, we investigated the effect of SIN on hepatic I/R injury, in particular its effect on heme oxygenase-1 (HO-1) induction and its hepatocellular protective effect. To our knowledge, our results were the first to show that: (a) SIN pretreatment was able to induce HO-1 expression in donor livers in a dose dependent manner; (b) SIN pretreatment protected the liver graft from cold I/R injury; and (c) the protective effect of SIN was, at least in part, mediated by HO-1, as proved by the fact that inhibiting HO-1 activity with zinc protoporphyrin (ZnPP) reduced the protection. Thus, SIN deserves further exploration as a novel agent to attenuate I/R injury.

Adjuvant treatment suppresses IL-17 production by T cell-independent myeloid sources in nonobese diabetic mice.

Recent studies have shown that Th17 cells, as a distinct lineage from Th1 and Th2 subsets, play an obligatory role in the pathogenesis of autoimmune diseases. It is well known that immunotherapy with Complete Freunds adjuvant (CFA) is effective in preventing from the onset of autoimmune diabetes in nonobese diabetic (NOD) mice. In the present study, we investigated whether CFA treatment restrained Th17 development and down-regulated Th17-related cytokine production in NOD mice. Th17-related cytokines (i.e. IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-6, TGF-beta) production in splenocytes was decreased dramatically on day 18 following CFA immunization. This effect was also observed at 10 and 20 week after adjuvant treatment. Injection of IL-17 into CFA-treated diabetes-free mice led to occurrence of overt diabetes, indicating that therapeutic effects of adjuvant treatment may be partially due to suppressing Th17 commitment. Interestingly, the main producer of IL-17 resided in a population of myeloid cells, which negatively expressed makers of neutrophil or macrophages. IL-23 stimulation did not alter the distribution of IL-17 in myeloid cells. Furthermore, this pattern of IL-17 expression was also present in Balb/c and C57BL/6 strains. These findings may have important implications for understanding of mechanisms underlying adjuvant treatment on autoimmune diseases.

A single-center retrospective analysis of liver transplantation on 255 patients with hepatocellular carcinoma.

Wang Z‐X, Song S‐H, Teng F, Wang G‐H, Guo W‐Y, Shi X‐M, Ma J, Wu Y‐M, Ding G‐S, Fu Z‐R. A single‐center retrospective analysis of liver transplantation on 255 patients with hepatocellular carcinoma. 
Clin Transplant 2010: 24: 752–757.

Near-term anti-CD25 monoclonal antibody administration protects murine liver from ischemia-reperfusion injury due to reduced numbers of CD4+ T cells.

Background CD4+ T cell is acknowledged as a key factor in the initiation phase of liver ischemia reperfusion injury. The purpose of current study is to demonstrate the effect of antecedent near-term anti-CD25 monoclonal antibody treatment on IR-induced liver injury by modulation of CD4+ T cells. Methods 70% liver warm IR was induced in male C57BL/6 mice after anti-CD25 mAb or non-specific IgG administration. Liver function, histological damage, in vitro Proliferation, FACS, cytokine production, and immunofluorescence were assessed to evaluate the impact of antecedent near-term PC61 treatment on IR-induced liver injury. Results After 70% liver ischemia, mice preconditioned with PC61 displayed significantly preserved liver function as characterized by less histological damage and reduced serum enzymes level. Mechanistic studies revealed that the protection effect of anti-CD25 mAb was associated with ameliorated intrahepatic inflammatory milieu and reduced CD4+ T lymphocytes as manifested by the decrease of proinflammatory cytokine production (less expression of TNF-α, IFN-γ, IL-2, and IL-6) and the lower CD4/CD8 proportion. Conclusions Our results provide first line of evidence indicating that near-term treatment with anti-CD25 monoclonal antibody might provide protection for livers against IR-induced injury by reducing CD4+ T cells, but not influencing functional Treg population. Therefore, our results demonstrate a potential function of anti-CD25 monoclonal antibody which was neglected in the past, and may be helpful in various clinical conditions, particularly in liver and kidney transplantations.

Regulatory effect of miR-144 on cytokine secretion in dendritic cells by targeting receptor activator of NF-κB ligand

Objective To investigate the effect of miRNA-144 on cytokine secretion by dendritic cells(DCs)during their maturation and the related mechanism.Methods miRNA chip results showed markedly down-regulated miRNA-144 during DCs maturation.The miR-144 level was also observed in DCs before and after treatment with lipopolysaccharide(LPS).The changes of related cytokines(TNF-α,IL-1β,IL-6and IL-23)and the activation of signaling pathway(NF-κB and MAPK)were detected in DCs after the transfection of miR-144.TargetScan was used to predict the target spot of miR-144 and double fluorescence reporting system was used for verification.Furthermore,we established DC2.4cell line stably overexpressing the target gene,and detected the TNF-αsecretion after transfecting miR-144 mimics.Results The miR-144 expression was significantly down-related in DCs stimulated with LPS(P0.01).After the miR-144 mimics were transfected into DCs,expressions of TNF-α,IL-1β,IL-6and IL-23 mRNA were significantly reduced(P 0.05,P 0.01),and NF-κB phosphorylation level was reduced as well.Bioinformatics analysis hinted that receptor activator of NF-κB ligand gene(RNAKL)was the potential target of miR-144,which was also validated by double fluorescence reporting system.Moreover,transfecting miR-144 mimics into DC2.4cells stably overexpressing RANKL resulted in no change of TNF-α mRNA expression.Conclusion miR-144 can regulate DCs cytokine secretion by targeting RANKL.