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

Clin Exp Med. 2009 Dec;9(4):269-76. doi: 10.1007/s10238-009-0052-2. Epub 2009 May 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Blotting, Western
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
  • CD4-Positive T-Lymphocytes / immunology*
  • Disease Models, Animal
  • Fas Ligand Protein / genetics
  • Fas Ligand Protein / metabolism
  • Female
  • Interferon Inducers / toxicity*
  • Liver Cirrhosis, Biliary / chemically induced
  • Liver Cirrhosis, Biliary / immunology*
  • Lymphocyte Activation*
  • Mice
  • Mice, Inbred C57BL
  • Poly I-C / toxicity*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • TNF-Related Apoptosis-Inducing Ligand / metabolism

Substances

  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Interferon Inducers
  • RNA, Messenger
  • TNF-Related Apoptosis-Inducing Ligand
  • Tnfsf10 protein, mouse
  • Poly I-C