Resistance to activation-induced cell death and elevated FLIPL expression of CD4+ T cells in a polyI:C-induced primary biliary cirrhosis mouse model

Abstract

Primary biliary cirrhosis (PBC) is a type of organ-specific autoimmune disease in which immune tolerance is impaired by an unknown mechanism. We established a PBC animal model by injecting C57BL/6 mice with polyI:C to study activation-induced cell death (AICD) in CD4+ T lymphocytes and changes of apoptosis-associated molecules as a first step to understand the immune tolerance of PBC mice. Obvious inflammatory cell infiltration was observed in the portal area of the liver tissues in model mice and antimitochondrial antibodies (AMA) positive rate was 80%. The AICD level in both splenic and hepatic CD4+ T cells in the model group were all lower than those in controls, and in the model group the level for hepatic CD4+ T cells were significantly lower than that for splenic CD4+ T cells. Quantitative PCR revealed that FasL mRNA and TRAIL expression in CD4+ T cells in the model group decreased significantly compared with that in the control group. Western blots revealed that the expression of the anti-apoptotic protein FLIP(L) in the model group increased significantly with the FLIP(L) expression in hepatic CD4+ T cells significantly higher than that in splenic CD4+ T cells. There was a positive linear correlation between the number of infiltrated portal areas and relative expression of FLIP(L) in splenic CD4+ T cells in model group. There were no obvious changes for caspase-8 in either group. These results show that the anti-apoptotic ability of CD4+ T lymphocytes play an important role in immune tolerance in the PBC mouse model, and elevated FLIP(L) expression may enhance this ability. The inhibition of FasL and TRAIL expression may also help enhance this anti-apoptotic ability in CD4+ T lymphocytes and contribute to the aggravation of portal area inflammation.

Effect of allogeneic bone marrow–derived mesenchymal stem cells transplantation in a polyI:C-induced primary biliary cirrhosis mouse model

“…In 2005, Okada et al [14] established an animal model conforming to PBC in terms of serological and histological characteristics by injecting with polyI:C, an IFN-a inducer, to C57BL/6 mice, and then the model was verified to have an elevated level of Fasassociated death domain-like interleukin-1-b-converting enzyme inhibitory protein L (FLIP L , an anti-apoptotic protein) in hepatic CD4 ? T cells, which contributed to the aggravation of portal area inflammation as human PBC [15]. In this study, we successfully repeated the animal model in the same way and discovered the general increase of aminotransferase and induction of autoimmune antibodies, especially the specific inflammation of liver tissues.…”

“…The establishment of PBC animal model was performed as described previously [14,15]. Mice in model group were injected with polyI:C (Sigma, USA) intraperitoneally at a concentration of 5 mg/kg body weight, twice a week for consecutive 16 weeks.…”

miR-17-92 expression in differentiated T cells - implications for cancer immunotherapy

“…We next examined whether transfection of Jurkat cells with miR-17-92 confers T cells resistant to AICD. AICD was induced by cultivation of Jurkat cells in the presence of 10 μg/ml anti-CD3 mAb, which is hyper-stimulatory and used as a standard method to induce AICD [38]. As demonstrated in (Fig.…”

Toll-Like Receptor 3 in Liver Diseases

“…A strong positive correlation between the mRNA levels of TLR3 and type I IFN in the liver was found in the patients with primary biliary cirrhosis, suggesting TLR3 signaling is involved in the pathogenesis of primary biliary cirrhosis [14]. In animal models, injection of poly I:C induced primary biliary cirrhosis-like cholangitis (such as infiltration of mononuclear cells and elevation of AMA autoantibodies) in a genetically susceptible mouse strain of female C57BL/6 mice [56, 57]. At present, the mechanisms by which poly I:C treatment induces cholangitis remain obscure.…”