The Role Of TNF-related Apoptosis-inducing Ligand In The Pathogenesis Of Systemic Lupus Erythematosus

Background Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by abnormally activated T cells-driven B cell hyperactivity and the production of a variety of autoantibodies. The aetiology of the disease remains unknown. There is increasing evidence that the presence and accumulation of abnormal apoptotic cell play a role in SLE patients. TNF-related apoptosis-inducing ligand (TRAIL) is a member of TNF family and has a well–documented role in mediating apoptosis of mailignant and viral infected cells. In recent years, there is growing evidence that TRAIL may involved in the pathogenesis of SLE. When death signals are transmitted, the cascade of caspases is set off and this ultimately leads to cell death. Caspase-3 is a major executioner protease and plays a crucial role in the transduction of apoptotic signals in cells. Nucleosome is generated during cell apoptosis and is found as a circulating complex in the sera of patients with SLE. Many studies have demonstrated the importance of nucleosome as major pathogenic autoantigen and it has been believed to play a key role in disease development in SLE. Although the important roles of TRAIL and nucleosome in the pathogenesis of SLE has been tested. However, it is not clear whether increased TRAIL levels may lead to apoptotic caspase activity increasing, and more nucleosome released, which may result in SLE activity. In this study, we tested this hypothesis by determining the levels of TRAIL mRNA expression, serum sTRAIL, activity of caspase-3 and levels of nucleosome released from PBMC in SLE patients. Furthermore, we explore the effects of TRAIL on apoptosis, the production of autoantibodies, and disease activity in systemic lupus erythematosus.Objective To investigate the effects of TRAIL on apoptosis, the production of autoantibodies, and disease activity in systemic lupus erythematosus (SLE).Methods Sixty patients with SLE and 20 healthy controls were enlisted. Semi-quantitative reverse transcription - polymerase chain reaction (RT-PCR) was used to measure the expression of TRAILmRNA on peripheral blood mononuclear cells (PBMC). The intracellular caspase-3 activity was determined by colorimetric assay. Concentration of serum sTRAIL, anti-nucleosome antibodies (AnuA) and nucleosomes released from PBMC were assayed by sandwich enzyme linked immunosorbent assay (ELISA).Results The expression levels of TRAILmRNA was significantly higher in active SLE patients (0.82±0.07) than inactive SLE patients (0.77±0.06) and healthy controls (0.75±0.05) (p<0.05).Caspase-3 activity (A405) was significantly higher in active SLE patients (0.53±0.28) than inactive SLE patients (0.39±0.23) and healthy controls (0.35±0.18) (p<0.05). The concentration of nucleosome released from PBMC was significantly higher in active SLE patients (3.09 (0.82～7.17) U/L) than inactive SLE patients (0.53 (0.33～1.78) U/L) and healthy controls (0.77 (0.58～0.96) U/L) (p<0.05). Serum sTRAIL concentration (μg/L)was significantly higher in active SLE patients (0.88±0.74) than inactive SLE patients (0.58±0.32) and healthy controls (0.48±0.28) (p < 0.05).There were significant positive correlations between TRAILmRNA expression and levels of serum sTRAIL, Caspase-3 activity (p<0.05), and between the Caspase-3 activity and levels of nucleosomes released from PBMC (p<0.05). There were positive correlations between TRAILmRNA expression and SLEDAI scores, anti-dsDNA, ESR, levels of serum AnuA concentration; negative correlations between TRAILmRNA expression and complement C4, lymphocyte counts; significant positive correlation between serum sTRAIL concentration and SLEDAI scores, negative correlation between sTRAIL concentration and lymphocyte counts. There were positive correlations between levels of nucleosome and SLEDAI scores, dsDNA, ESR, levels of AnuA; negative correlations with complement C3, C4, lymphocyte counts.Conclusion The mean expression levels of TRAILmRNA on PBMC and serum sTRAIL levels were increased in SLE patients. TRAIL-mediated apoptosis may participate in the abnormal apoptosis of PBMC, increased nucleosome release and disease activity in SLE patients.