CRFR1 activation protects against cytokine-induced beta cell death

TY - JOUR

T1 - CRFR1 activation protects against cytokine-induced beta cell death

AU - Blaabjerg, Lykke

AU - Christensen, Gitte Lund

AU - Matsumoto, Masahito

AU - van der Meulen, Talitha

AU - Huising, Mark O

AU - Billestrup, Nils

AU - Vale, Wylie

PY - 2014/10/16

Y1 - 2014/10/16

N2 - During the development of diabetes b-cells are exposed to elevated concentrations of proinflammatory cytokines, TNFa and IL1b, which in vitro induce b-cell death. The class B G-protein-coupled receptors (GPCRs): corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 are expressed in pancreatic islets. As downstream signaling by other class B GPCRs can protect against cytokine-induced b-cell apoptosis, we evaluated the protective potential of CRFR activation in b-cells in a pro-inflammatory setting. CRFR1/CRFR2 ligands activated AKT and CRFR1 signaling and reduced apoptosis in human islets. In rat and mouse insulin-secreting cell lines (INS-1 and MIN6), CRFR1 agonists upregulated insulin receptor substrate 2 (IRS2) expression, increased AKT activation, counteracted the cytokine-mediated decrease in BAD phosphorylation, and inhibited apoptosis. The anti-apoptotic signaling was dependent on prolonged exposure to corticotropin-releasing factor family peptides and followed PKA-mediated IRS2 upregulation. This indicates that CRFR signaling counteracts proinflammatory cytokine-mediated apoptotic pathways through upregulation of survival signaling in b-cells. Interestingly, CRFR signaling also counteracted basal apoptosis in both cultured INS-1 cells and intact human islets.

AB - During the development of diabetes b-cells are exposed to elevated concentrations of proinflammatory cytokines, TNFa and IL1b, which in vitro induce b-cell death. The class B G-protein-coupled receptors (GPCRs): corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 are expressed in pancreatic islets. As downstream signaling by other class B GPCRs can protect against cytokine-induced b-cell apoptosis, we evaluated the protective potential of CRFR activation in b-cells in a pro-inflammatory setting. CRFR1/CRFR2 ligands activated AKT and CRFR1 signaling and reduced apoptosis in human islets. In rat and mouse insulin-secreting cell lines (INS-1 and MIN6), CRFR1 agonists upregulated insulin receptor substrate 2 (IRS2) expression, increased AKT activation, counteracted the cytokine-mediated decrease in BAD phosphorylation, and inhibited apoptosis. The anti-apoptotic signaling was dependent on prolonged exposure to corticotropin-releasing factor family peptides and followed PKA-mediated IRS2 upregulation. This indicates that CRFR signaling counteracts proinflammatory cytokine-mediated apoptotic pathways through upregulation of survival signaling in b-cells. Interestingly, CRFR signaling also counteracted basal apoptosis in both cultured INS-1 cells and intact human islets.

U2 - 10.1530/JME-14-0056

DO - 10.1530/JME-14-0056

M3 - Journal article

C2 - 25324488

SN - 0952-5041

VL - 53

SP - 417

EP - 427

JO - Journal of Molecular Endocrinology

JF - Journal of Molecular Endocrinology

ER -