title: CRFR1 activation protects against cytokine-induced β-cell death.
abstract: During the development of diabetes β-cells are exposed to elevated concentrations of proinflammatory cytokines, TNFα and IL1β, which in vitro induce β-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 β-cell apoptosis, we evaluated the protective potential of CRFR activation in β-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 β-cells. Interestingly, CRFR signaling also counteracted basal apoptosis in both cultured INS-1 cells and intact human islets.
authors.affiliation: Clayton Foundation Laboratories for Peptide BiologySalk Institute, 10100 North Torrey Pines Road, La Jolla, California 92037, USACellular and Metabolic Research SectionDepartment of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark Clayton Foundation Laboratories for Peptide BiologySalk Institute, 10100 North Torrey Pines Road, La Jolla, California 92037, USACellular and Metabolic Research SectionDepartment of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark lykke@blaabjerg.net.
authors.forename: Lykke
authors.initials: L
authors.lastname: Blaabjerg
authors.affiliation: Clayton Foundation Laboratories for Peptide BiologySalk Institute, 10100 North Torrey Pines Road, La Jolla, California 92037, USACellular and Metabolic Research SectionDepartment of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
authors.forename: Gitte L
authors.initials: GL
authors.lastname: Christensen
authors.affiliation: Clayton Foundation Laboratories for Peptide BiologySalk Institute, 10100 North Torrey Pines Road, La Jolla, California 92037, USACellular and Metabolic Research SectionDepartment of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
authors.forename: Masahito
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Clayton Foundation Laboratories for Peptide BiologySalk Institute, 10100 North Torrey Pines Road, La Jolla, California 92037, USACellular and Metabolic Research SectionDepartment of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
authors.forename: Talitha
authors.initials: T
authors.lastname: van der Meulen
authors.affiliation: Clayton Foundation Laboratories for Peptide BiologySalk Institute, 10100 North Torrey Pines Road, La Jolla, California 92037, USACellular and Metabolic Research SectionDepartment of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Huising
authors.affiliation: Clayton Foundation Laboratories for Peptide BiologySalk Institute, 10100 North Torrey Pines Road, La Jolla, California 92037, USACellular and Metabolic Research SectionDepartment of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
authors.forename: Nils
authors.initials: N
authors.lastname: Billestrup
authors.affiliation: Clayton Foundation Laboratories for Peptide BiologySalk Institute, 10100 North Torrey Pines Road, La Jolla, California 92037, USACellular and Metabolic Research SectionDepartment of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
authors.forename: Wylie W
authors.initials: WW
authors.lastname: Vale
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D016207:Cytokines / Q000009:adverse effects*; D019610:Cytoprotection / Q000187:drug effects*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D053583:Interleukin-1beta / Q000009:adverse effects; D051379:Mice; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists*; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects; D000099052:CRF Receptor, Type 1
chemical_list: D016207:Cytokines; C508585:IL1B protein, human; D053583:Interleukin-1beta; D018019:Receptors, Corticotropin-Releasing Hormone; D014409:Tumor Necrosis Factor-alpha; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone
keywords: CRFR; GPCR; apoptosis; cytokines; survival; urocortins; β cells