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CHOP deletion does not impact the development of diabetes but suppresses the early production of insulin autoantibody in the NOD mouse

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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.

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Acknowledgments

We would like to thank M. Motomura and Y. Kataoka for their technical assistance. This study was supported by research grants from the Japan Society for the Promotion of Science (#21591143, #22930032, #21790874, #22790865).

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan

    T. Satoh, N. Abiru, M. Kobayashi, H. Zhou, K. Nakamura, G. Kuriya & K. Eguchi

  2. Department of Immunology and Rheumatology, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    H. Nakamura & K. Eguchi

  3. Department of Medical Gene Technology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Y. Nagayama

  4. Metabolism/Diabetes and Clinical Nutrition, Nagasaki University Hospital, Nagasaki, Japan

    E. Kawasaki

  5. Center for Health and Community Medicine, Nagasaki University, Nagasaki, Japan

    H. Yamasaki

  6. Barbara Davis Center for Childhood Diabetes, UCHSC, Denver, CO, USA

    L. Yu & G. S. Eisenbarth

  7. Department of Metabolic Medicine, Kumamoto University School of Medicine, Kumamoto, Japan

    E. Araki

  8. Laboratory of Molecular Genetics, Faculty of Pharmaceutical Sciences Sojo University, Kumamoto, Japan

    M. Mori

  9. Division of Molecular Biology Institute for Genome Research, The University of Tokushima, Tokushima, Japan

    S. Oyadomari

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  1. T. Satoh
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  2. N. Abiru
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  3. M. Kobayashi
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  15. S. Oyadomari
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Correspondence to N. Abiru.

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Satoh, T., Abiru, N., Kobayashi, M. et al. CHOP deletion does not impact the development of diabetes but suppresses the early production of insulin autoantibody in the NOD mouse. Apoptosis 16, 438–448 (2011). https://doi.org/10.1007/s10495-011-0576-2

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