Document Type : Original Article
Authors
- Eisa Salehi 1
- Mohammad Vodjgani 1
- Ahmad massoud 1
- Abdolhosein Keyhani 1
- Asadollah Rajab 2
- Behrooz Shafaghi 3
- Zahra Gheflati 1
- Tahereh Aboufazeli 1
1 Department of Immunology, Tehran University of Medical Sciences
2 Iranian Diabetes Society
3 Shahid Beheshti University of Medical Sciences, Tehran, Iran
Abstract
Background: Type-I diabetes is an autoimmune inflammatory disease in which pancreatic ß-cells are selectively destroyed by infiltrating cells. TNF-related apoptosis-inducing ligand (TRAIL) is a type-II membrane protein of the TNF superfamily which is expressed in different tissues, including pancreas and lymphocytes. In humans, TRAIL interacts with four membrane receptors. TRAIL-R1 and TRAIL-R2 have cytoplasmic death domains, and can activate both caspases and NFκB pathways. The other two receptors, TRAIL-R3 and TRAIL-R4, are decoy receptors not capable of activating caspase cascade but may activate NF-κB and block apoptosis. As human beta cells are sensitive to TRAIL induced apoptosis, signaling via these molecules is considered to be a probable way of beta cell destruction. These molecules also are important in suppression of autorective T cells and immunoregulation.
Objective: To explore the importance of TRAIL and its receptors at pathogenesis of type-I diabetes, we compared expression of these molecules on T-cells of diabetic patients and healthy controls.
Methods: In this study, expression of TRAIL and its receptors at protein and mRNA levels were studied in freshly isolated peripheral T cells of 55 type I diabetic patients and 50 healthy individuals by flowcytometry, western blot and RT-PCR.
Results: We found that expression of TRAIL and its receptors in peripheral T-cells at both protein and mRNA levels are significantly increased in patients (except for TRAIL-R2 mRNA which was slightly higher in controls) but increase in TRAIL, TRAIL-R3 (2.7% vs. >0.5%) and TRAIL-R4 (2.6% vs. >0.5%) is more considerable. sTRAIL in sera of patients was significantly lower than in controls (p=0.01).
Conclusion: Our results explain resistance of autoreactive T-cells to immunoregulatory mechanisms. Besides, increased expression of TRAIL in autoreactive T-cells may play an important role in beta-cell destruction. Lower level of sTRAIL in diabetic patients may be a reason for hyperactivation of autoreactive T-cells.
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