Dendritic cells with increased expression of suppressor of cytokine signaling 1(SOCS1) gene ameliorate lipopolysaccharide/d-galactosamine-induced acute liver failure.

Acute liver failure is a devastating clinical syndrome with extremely terrible inflammation reaction, which is still lack of effective treatment in clinic. Suppressor of Cytokine Signaling 1 protein is inducible intracellular negative regulator of Janus kinases (JAK)/signal transducers and activators of transcription (STAT) pathway that plays essential role in inhibiting excessive intracellular signaling cascade and preventing autoimmune reaction. In this paper, we want to explore whether dendritic cells (DCs) with overexpression of SOCS1 have a therapeutic effect on experimental acute liver failure. Bone marrow derived dendritic cells were transfected with lentivirus encoding SOCS1 and negative control lentivirus, thereafter collected for costimulatory molecules analysis, allogeneic Mixed Lymphocyte Reaction and Western blot test of JAK/STAT pathway. C57BL/6 mice were randomly separated into normal control and treatment groups which respectively received tail vein injection of modified DCs, negative control DCs and normal saline 12 h earlier than acute liver failure induction. Our results indicated that DCs with overexpression of SOCS1 exhibited like regulatory DCs (DCregs) with low level of costimulatory molecules and poor allostimulatory ability in vitro, which was supposed to correlate with block of JAK2/STAT1 signaling. In vivo tests, we found that infusion of modified DCs increased survival rate of acute liver failure mice and alleviate liver injury via inhibition of TLR4/HMGB1 pathway. We concluded that DCs transduced with SOCS1 gene exhibit as DCregs through negative regulation of JAK2/STAT1 pathway and ameliorated lipopolysaccharide/d-galactosamine induced acute liver failure via inhibition of TLR4 pathway.

Splenic CD11c(low)CD45RB(high) dendritic cells derived from endotoxin-tolerant mice attenuate experimental acute liver failure.

Endotoxin tolerance (ET) is suggested to attenuate the severity of acute liver failure (ALF) in mice, possibly through both innate and adaptive immunity. However, the involvement of regulatory dendritic cells (DCregs) in ET has not been fully elucidated. In this study, their effect on ALF in mice was investigated. Splenic DCregs from ET-exposed mice (ET-DCregs) showed lower expression levels of CD40, CD80, and MHC-II markers and stronger inhibition of allogenic T cells and regulation of IL-10 and IL-12 secretion than splenic DCregs from normal mice (nDCregs). Moreover, the mRNA and protein levels of TNF-α and P65 in splenic ET-DCregs were significantly lower than those in the splenic nDCregs. The survival rate was significantly increased and liver injury was mitigated in mice with ALF treated with splenic ET-DCregs. In addition, A20 expression was decreased in the liver of ALF mice, but elevated after infusion of splenic nDCregs and ET-DCregs, and a much higher elevation was observed after infusing the latter cells. The functionality of splenic DCregs was altered after ET exposure, contributing to protection of the livers against D-GalN/LPS-induced ALF.

[Experimental correlation study of lumbar spinal stenosis and knee joint degeneration].

OBJECTIVE: To explore the correlation of lumbar stenosis and knee osteoarthritis by establishing a rabbit lumbar spinal stenosis model and observing the hind limb movement function and pathological change of articular cartilage of knee joint. METHODS: A total of 36 healthy adult rabbits were randomly divided into model group and control group. In the model group, spinal canal was filled with bone pieces to make lumbar spinal stenosis; in the control group, sham operation was performed and materials were inserted into spinal canal. Movement function was evaluated by Tarlov method and pathological features were observed by Mankin's scores under light microscope at 4, 8 and 12 weeks. RESULTS: Early degenerative changes of knee cartilage were observed in the model group at 4 and 8 weeks post-operation. There were synovial hyperemia and hyperplasia, increased synovial fluid effusion and lightly-stained cartilage. The Mankin score was 3.3 - 4.5 and Tarlov score 3 - 4. Intermediate stage changes of osteoarthritis were found in the model group at 12 weeks post-operation, showing synovial hyperplasia, decreased synovial fluid, fissure in cartilage surface, tangled cartilage cells and unevenly stained matrix. The Mankins score was 7 - 9 and Tarlov score 2 - 3. Most of articular cartilage was normal in the control group with Mankin score of 0 - 1 and Tarlov score of 4. CONCLUSION: Lumbar stenosis may be correlated with knee joint degeneration.