https://doi.org/10.1530/JME-20-0238 https://jme.bioscientifca.com © 2021 Society for Endocrinology Printed in Great Britain Published by Bioscientifca Ltd. Dexamethasone induces β-cell apoptosis K Suksri et al. Journal of Molecular Endocrinology 95–106 67 3 : RESEARCH Dexamethasone induces pancreatic β-cell apoptosis through upregulation of TRAIL death receptor Kanchana Suksri 1 , Namoiy Semprasert 1 , Mutita Junking 2 , Suchanoot Kutpruek 1 , Thawornchai Limjindaporn 3 , Pa-thai Yenchitsomanus 2 and Suwattanee Kooptiwut 1 1 Department of Physiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand 2 Division of Molecular Medicine, Research Department, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand 3 Department of Anatomy, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand Correspondence should be addressed to S Kooptiwut: S_kooptiwut@hotmail.com Abstract Long-term medication with dexamethasone – a synthetic glucocorticoid (GC) drug – results in hyperglycemia, or steroid-induced diabetes. Although recent studies revealed that dexamethasone directly induces pancreatic β-cell apoptosis, its molecular mechanisms remain unclear. In our initial analysis of mRNA transcripts, we discovered the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway may be involved in dexamethasone-induced pancreatic β-cell apoptosis. In the present study, a mechanism of dexamethasone-induced pancreatic β-cell apoptosis through the TRAIL pathway was investigated in cultured cells and isolated mouse islets. INS-1 cells were cultured with and without dexamethasone in the presence or absence of a glucocorticoid receptor (GR) inhibitor, RU486. We found that dexamethasone induced pancreatic β-cell apoptosis in association with the upregulation of TNSF10 (TRAIL) mRNA and protein expression. Moreover, dexamethasone upregulated the TRAIL death receptor (DR5) protein but suppressed the decoy receptor (DcR1) protein. Similar fndings were observed in mouse isolated islets: dexamethasone increased TRAIL and DR5 compared to that of control mice. Furthermore, dexamethasone stimulated pro-apoptotic signaling including superoxide production, caspase-8, -9, and -3 activities, NF-κB, and Bax but repressed the anti-apoptotic protein, Bcl-2. All these efects were inhibited by the GR-inhibitor, RU486. Furthermore, knock-down DR5 decreased dexamethasone-induced caspase 3 activity. Caspase-8 and caspase-9 inhibitors protected pancreatic β-cells from dexamethasone- induced apoptosis. Taken together, dexamethasone induced pancreatic β-cell apoptosis by binding to the GR and inducing DR5 and TRAIL pathway. Introduction Glucocorticoids (GCs) are a group of steroid drugs that exert strong anti-infammatory and immunosuppressive efects. The synthetic GCs include dexamethasone and prednisolone, which are currently in clinical use for the treatment of several diseases (Clore & Thurby-Hay 2009). Long-term medication with GCs can cause hyperglycemia with or without diabetes (Clore & Thurby-Hay 2009). The time and dosage of GC medication are associated with Journal of Molecular Endocrinology (2021) 67, 95–106 Key Words f dexamethasone f pancreatic β-cells f TRAIL f apoptosis f glucocorticoid receptor Downloaded from Bioscientifica.com at 06/16/2023 01:54:35PM via free access