Increased Expression of TRAIL and Its Receptors on Peripheral T-cells in Type 1 Diabetic Patients
Type-I diabetes is an autoimmune inflammatory disease in which pancreatic beta-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 NFkappaB pathways. The other two receptors, TRAIL-R3 and TRAIL-R4, are decoy receptors not capable of activating caspase cascade but may activate NF-kappaB 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.



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.



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.



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).



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.
Salehi
Eisa
E
Department of Immunology, Tehran University of Medical Sciences, Tehran, Iran.
Vodjgani
Mohammad
M
Massoud
Ahmad
A
Keyhani
Abdolhosein
A
Rajab
Asadollah
A
Shafaghi
Behrooz
B
Gheflati
Zahra
Z
Aboufazeli
Tahereh
T
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D012995:Solubility; D013601:T-Lymphocytes / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand