title: CHOP deletion does not impact the development of diabetes but suppresses the early production of insulin autoantibody in the NOD mouse.
abstract: C/EBP homologous protein (CHOP) has been proposed as a key transcription factor for endoplasmic reticulum (ER) stress-mediated β-cell death induced by inflammatory cytokines in vitro. However, the contribution of CHOP induction to the pathogenesis of type 1 diabetes is not yet clear. To evaluate the relevance of CHOP in the pathogenesis of type 1 diabetes in vivo, we generated CHOP-deficient non-obese diabetic (NOD.Chop (-/-)) mice. CHOP deficiency did not affect the development of insulitis and diabetes and apoptosis in β-cells. Interestingly, NOD.Chop (-/-) mice exhibited a delayed appearance of insulin autoantibodies compared to wild-type (wt) mice. Adoptive transfer with the diabetogenic, whole or CD8(+)-depleted splenocytes induced β-cell apoptosis and the rapid onset of diabetes in the irradiated NOD.Chop (-/-) recipients with similar kinetics as in wt mice. Expression of ER stress-associated genes was not significantly up-regulated in the islets from NOD.Chop (-/-) compared to those from wt mice or NOD-scid mice. These findings suggest that CHOP expression is independent of the development of insulitis and diabetes but might affect the early production of insulin autoantibodies in the NOD mouse.
authors.affiliation: Department of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Satoh
authors.forename: N
authors.initials: N
authors.lastname: Abiru
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.forename: K
authors.initials: K
authors.lastname: Nakamura
authors.forename: G
authors.initials: G
authors.lastname: Kuriya
authors.forename: H
authors.initials: H
authors.lastname: Nakamura
authors.forename: Y
authors.initials: Y
authors.lastname: Nagayama
authors.forename: E
authors.initials: E
authors.lastname: Kawasaki
authors.forename: H
authors.initials: H
authors.lastname: Yamasaki
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.forename: G S
authors.initials: GS
authors.lastname: Eisenbarth
authors.forename: E
authors.initials: E
authors.lastname: Araki
authors.forename: M
authors.initials: M
authors.lastname: Mori
authors.forename: S
authors.initials: S
authors.lastname: Oyadomari
authors.forename: K
authors.initials: K
authors.lastname: Eguchi
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D001323:Autoantibodies / Q000096:biosynthesis* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000473:pathology; D017353:Gene Deletion; D005786:Gene Expression Regulation; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000276:immunology*; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D008212:Lymphocyte Depletion; D051379:Mice; D016688:Mice, Inbred NOD; D009195:Peroxidase / Q000378:metabolism; D011236:Prediabetic State / Q000276:immunology* / Q000473:pathology*; D013154:Spleen / Q000276:immunology; D013312:Stress, Physiological / Q000235:genetics; D051742:Transcription Factor CHOP / Q000235:genetics* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; C497250:Ddit3 protein, mouse; D007328:Insulin; D051742:Transcription Factor CHOP; D009195:Peroxidase