Dexamethasone induces pancreatic β-cell apoptosis through upregulation of TRAIL death receptor

Abstract

Long-term medication with dexamethasone (a synthetic glucocorticoid (GC) drug) results in hyperglycemia, or steroid-induced diabetes. Although recent studies revealed 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 TRAIL mRNA and protein expression. Moreover, dexamethasone upregulated the TRAIL death receptor (DR5) protein but suppressed the decoy receptor (DcR1) protein. Similar findings 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-B, and Bax, but repressed the anti-apoptotic protein, Bcl-2. All these effects 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.

Imatinib protects against dexamethasone-induced pancreatic β-cell apoptosis via downregulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and death receptor 5 (DR5)

“…A common terminal enzyme of both the extrinsic and intrinsic apoptotic pathways is caspase-3. In a previously published work, our research group demonstrated that dexamethasone increased caspase-3 activity [25]. Other studies reported that dexamethasone increased caspase-3 expression and activity in several cell types, including goat epithelial cells, human cancer cells, and mouse MIN 6 cells [12,59,60]…”

“…Long-term dexamethasone use can cause steroid-induced diabetes, and imatinib was previously reported to ameliorate diabetes in patients with chronic myeloid leukemia (CML). In addition, dexamethasone could induce pancreatic β-cell apoptosis via upregulation of TRAIL and its receptor -DR5 [25]. We, therefore, hypothesized that imatinib will protect against dexamethasone-induced pancreatic β−cell apoptosis via downregulation of TRAIL and DR5, which effectuates favorable effect on downstream molecules in apoptotic pathways.…”

“…Taken together, GC reduces pancreatic β-cell population by inducing pancreatic β-cell apoptosis and inhibiting pancreatic β-cell proliferation [23,24]. Our research group recently demonstrated that dexamethasone could upregulate TRAIL and its death receptor (DR5) [25], which suggests that dexamethasone can induce pancreatic β-cell apoptosis via upregulation of TRAIL and DR5.…”

Imatinib prevents dexamethasone‐induced pancreatic β‐cell apoptosis via decreased TRAIL and DR5

“…Long‐term dexamethasone use can cause steroid‐induced diabetes , and imatinib was previously reported to ameliorate diabetes in patients with CML. In addition, dexamethasone could induce pancreatic β‐cell apoptosis via upregulation of TRAIL and its receptor—DR5 21 . We, therefore, hypothesized that imatinib will protect against dexamethasone‐induced pancreatic β−cell apoptosis via downregulation of TRAIL and DR5, which effectuates favorable effect on downstream molecules in apoptotic pathways.…”

Underlying mechanisms of glucocorticoid-induced β-cell death and dysfunction: a new role for glycogen synthase kinase 3

“…The underlying mechanisms of the GC-mediated β-cell apoptosis are only partially known. It is generally admitted that this process takes place mostly through the activation of the intrinsic apoptotic pathway in β-cells [ 19 , 39 , 40 ], although one study showed recently an effect on the extrinsic pathway [ 41 ]. We therefore investigated the expression of members of bcl-2 family of proteins, namely Bim and Bcl-2, which are key players in the GC-induced intrinsic apoptotic pathway [ 19 , 40 ].…”