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Feng M.,Nanjing Medical University | Wang Q.,Nanjing Medical University | Wang Q.,Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health | Jiang Z.,Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health | And 5 more authors.
Clinical Immunology | Year: 2016

Our study showed that hepatic stellate cells (HSCs) promote the healing of the liver after drug-induced acute injury. However, the relevant mechanisms by which this is accomplished remain unclear. The objective of this study was to investigate the role of the adoptive transfer of HSCs in acute liver injury and the underlying mechanisms for healing. It was found that adoptive transfer of HSCs resulted in an increase in Tregs and a decrease in Th17 cells. Liver insult was consistently attenuated by HSC treatment. HSC cultured medium induced Tregs from naive T cells and suppressed the differentiation of Th17 cells. This study demonstrated that the adoptive transfer of HSCs protected the liver from drug-induced acute injury. Promoting the differentiation of Tregs and suppressing the development of Th17 cells are possibly involved in the protective effect of adoptive transfer of HSCs. © 2016 Elsevier Inc.

Feng M.,Nanjing Medical University | Feng M.,Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health | Wang Q.,Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health | Wang Q.,Nanjing Medical University | And 4 more authors.
International Immunopharmacology | Year: 2012

In the presence of TGF-β, CD4+CD62L+T cells can be induced to CD4+CD25+FoxP3 + regulatory T cells (iTregs). In our previous work, we have shown that adoptive transfer of iTregs promoted liver recovery from ischemia reperfusion injury (IRI). In this study, we examined the molecular mechanism underlying the liver IRI attenuation by iTregs in a mouse partial hepatic IRI model. We found that the population of hepatic Tregs decreased significantly at 24 h after reperfusion. Adoptive transfer of iTregs before IRI markedly increased the numbers of hepatic Tregs and attenuated liver IRI as indicated by reduced serum aminotransferases and proinflammatory cytokines, such as interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α). Ex vivo study indicated that iTregs suppressed IL-1β and TNF-α expression, promoted transcription of interleukin-10 (IL-10), and elevated phosphorylation of SMAD3 in Kupffer cells (KCs). Furthermore, inhibition of TGF-β signaling by anti-TGF-β abolished the effects on KCs. Treatment with TGF-β suppressed matrix metalloprotease (MMP9) production in KCs and protected liver from IRI. In conclusion, our results suggest that iTregs play a critical role in hepatic IRI by regulating pro-inflammatory and anti-inflammatory function of KCs through TGF-β. © 2011 Elsevier B.V. All rights reserved.

Zhou B.,Nanjing Medical University | Zhou B.,Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health | Fan Y.,Nanjing Medical University | Fan Y.,Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health | And 10 more authors.
Journal of Surgical Research | Year: 2015

Background Liver regeneration is a complex process regulated by many complex mechanisms involving cytokines, growth factors, metabolic networks, and so forth. Previous investigations have demonstrated that matrix metalloproteinase-9 (MMP-9) is an essential factor in liver regeneration. The present study aimed to explore the role of MMP-9 in epidermal growth factor receptor (EGFR) signaling and related proliferation signaling factors in a mouse partial hepatectomy (PH) model. Materials and methods MMP-9 knockout (KO) and wild-type mice were used to establish the PH model. Liver regeneration was analyzed based on proliferation cell nuclear antigen immunohistochemistry and liver weight to body weight ratio. Also, EGFR ligands, EGFR, and downstream factors were measured by quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot. Results MMP-9 KO mice showed a delayed hepatic regenerative response after PH. EGFR ligands, including heparin-binding epidermal growth factor and amphiregulin, were expressed at significantly lower levels between days 1 and 3 posthepatectomy in MMP-9 KO mice. MMP-9 KO mice also inhibited and delayed EGFR activation after PH. After PH, the expression of STAT3, NF-κB, and cyclinD1, all downstream of EGFR, was similar to EGFR activation. Conclusions Our data provide new evidence supporting a critical role of MMP-9 in liver regeneration after PH through activation of EGFR signaling. © 2015 Elsevier Inc. All rights reserved.

Rao J.,Nanjing Medical University | Rao J.,Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health | Qin J.,Nanjing Medical University | Qin J.,Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health | And 16 more authors.
PLoS ONE | Year: 2013

Background:Low-dose lipopolysaccharide (LPS) preconditioning-induced liver protection has been demonstrated during ischemia-reperfusion injury (IRI) in several organs but has not been sufficiently elucidated underlying causal mechanism. This study investigated the role of low-dose LPS preconditioning on ATF4-CHOP pathway as well as the effects of the pathway on tissue injury and inflammation in a mouse model of liver partial-warm IRI.Methods:LPS (100 μg/kg/d) was injected intraperitoneally two days before ischemia. Hepatic injury was evaluated based on serum alanine aminotransferase levels, histopathology, and caspase-3 activity. The ATF4-CHOP pathway and its related apoptotic molecules were investigated after reperfusion. The role of LPS preconditioning on apoptosis and ATF4-CHOP pathway was examined in vitro. Moreover, the effects of the ATF4-CHOP pathway on apoptosis, Caspase-12, and Caspase-3 were determined with ATF4 small interfering RNA (siRNA). Inflammatory cytokine expression was also checked after reperfusion. Inflammatory cytokines and related signaling pathways were analyzed in vitro in macrophages treated by LPS preconditioning or ATF4 siRNA.Results:LPS preconditioning significantly attenuated liver injury after IRI. As demonstrated by in vitro experiments, LPS preconditioning significantly reduced the upregulation of the ATF4-CHOP pathway and inhibited Caspase-12 and Caspase-3 activation after IRI. Later experiments showed that ATF4 knockdown significantly suppressed CHOP, cleaved caspase-12 and caspase-3 expression, as well as inhibited hepatocellular apoptosis. In addition, in mice pretreated with LPS, TNF-α and IL-6 were inhibited after reperfusion, whereas IL-10 was upregulated. Similarly, low-dose LPS significantly inhibited TNF-α, IL-6, ATF4-CHOP pathway, NF-κB pathway, and ERK1/2 in high-dose LPS-stimulated macrophages, whereas IL-10 and cytokine signaling (SOCS)-3 suppressor were induced. Importantly, ATF4 siRNA is consistent with results of LPS preconditioning in macrophages.Conclusions:This work is the first time to provide evidence for LPS preconditioning protects hepatocytes from IRI through inhibiting ATF4-CHOP pathway, which may be critical to reducing related apoptosis molecules and modulating innate inflammation. © 2013 Rao et al.

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