The role of thioredoxin 1 in the mycophenolic acid-induced apoptosis of insulin-producing cells

K H Huh,Y Cho,Y S Kim,B S Kim,Y-J Park,J H Do,M S Kim,D J Joo

doi:10.1038/cddis.2013.247

Abstract

Mycophenolic acid (MPA) is one of many effective immunosuppressive drugs. However, MPA can induce cellular toxicity and impair cellular function in β-cells. To explore the effects of MPA and the relation between MPA and Trx-1, we used various methods, including an Illumina microarray, to identify the genes regulated during pancreatic β-cell death following MPA treatment. INS-1E cells (a pancreatic β-cell line) and isolated rat islets were treated with MPA for 12, 24, or 36 h, and subsequent microarray analysis showed that (Trx1) gene expression was significantly reduced by MPA. Further, Trx1 overexpression increased the cell viability, decreased the activations of c-jun N-terminal kinase (JNK) and caspase-3 by MPA, and attenuated ROS upregulation by MPA. Furthermore, siRNA knockdown of Trx1 increased MPA-induced cell death and the activations of p-JNK and caspase-3, and MPA significantly provoked the apoptosis of insulin-secreting cells via Trx1 downregulation. Our findings suggest that the prevention of Trx1 downregulation in response to MPA is critical for successful islet transplantation.

Highlights

Prolonged guanosine triphosphate (GTP) depletion induces the apoptosis of insulin-secreting cells.[6,7,8] Recently, it was suggested that Mycophenolic acid (MPA)-mediated GTP depletion blocks DNA synthesis and induces b-cell death,[6,7,9,10] but the mechanism responsible for MPA-induced b-cell death was not determined
This analysis confirmed that Trx[1] gene expression was decreased by MPA (Table 1). These findings suggest that the downregulation of Trx[1] by MPA in INS-1E cells is associated with MPA-induced b-cell apoptosis
We found that MPA induced apoptosis in several pancreatic b-cell lines via jun N-terminal kinase (JNK) activation,[12,13,37] and we investigated the effect of Trx[1] expression on the MAPK signaling pathway

Summary

Introduction

Prolonged guanosine triphosphate (GTP) depletion induces the apoptosis of insulin-secreting cells.[6,7,8] Recently, it was suggested that MPA-mediated GTP depletion blocks DNA synthesis and induces b-cell death,[6,7,9,10] but the mechanism responsible for MPA-induced b-cell death was not determined. We previously reported the specific depletion of GTP via the MPA-induced apoptosis of insulin-secreting cells (HIT-T15, RIN-5, INS-1E, and isolated rat islets) and confirmed that co-treatment with GTP completely blocked. The expressions of 386 genes in INS-1E cells and of 234 genes in primary rat islet cells were found to be significantly altered by MPA as determined using an Illumina cDNA microarray.[13] Further, the expressions of some genes, such as, RhoGDI-a, Thioredoxin 1 (Trx1), Bcl2-related protein, and programmed cell death 2 (pdcd 2), are known to be closely related to MPA-induced b-cell death.[13,14,15]. Received 04.3.13; revised 07.6.13; accepted 07.6.13; Edited by A Stephanou (Gpx-1, which detoxifies H2O2), and Trx.[27,28] Further, the preventions of autoimmune and STZ-induced diabetes by Trx[1] overexpression in b-cells suggest that Trx[1] has important effects on b-cell destruction in type 1 diabetes (T1D) and on genetic susceptibility to T1D,27,29 and indicate that Trx[1] has a critical role during b-cell death in T1D

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