TY - JOUR
T1 - Impaired upregulation of Stat2 gene restrictive to pancreatic β-cells is responsible for virus-induced diabetes in DBA/2 mice
AU - Mine, Keiichiro
AU - Nagafuchi, Seiho
AU - Hatano, Shinya
AU - Tanaka, Kenichi
AU - Mori, Hitoe
AU - Takahashi, Hirokazu
AU - Anzai, Keizo
AU - Yoshikai, Yasunobu
N1 - Funding Information:
The authors are grateful to N. Noguchi, H. Yamada, T. Murakami, X. Tun, and D. Yue for giving counsel about experiments, and Y. Kitada, A. Yano, and C. Ogawa for helping to prepare the manuscript, and K. Ichikawa for helping the histopathology experiments. We appreciate the technical support by the Research Support Center, Graduate School of Medical Sciences, Kyushu University; Laboratory for Technical Support, Medical Institute of Bioregulation, Kyushu University; and Analytical Research Center for Experimental Sciences, Saga University. This work was supported by a Grant-in-Aid for JSPS Fellows [17J03060], a Grant-in-Aid for Scientific Research B [18H02853], and a Japan IDDM Network Research Grant.
Funding Information:
The authors are grateful to N. Noguchi, H. Yamada, T. Murakami, X. Tun, and D. Yue for giving counsel about experiments, and Y. Kitada, A. Yano, and C. Ogawa for helping to prepare the manuscript, and K. Ichikawa for helping the histopathology experiments. We appreciate the technical support by the Research Support Center, Graduate School of Medical Sciences, Kyushu University; Laboratory for Technical Support, Medical Institute of Bioregulation, Kyushu University; and Analytical Research Center for Experimental Sciences, Saga University. This work was supported by a Grant-in-Aid for JSPS Fellows [ 17J03060 ], a Grant-in- Aid for Scientific Research B [ 18H02853 ], and a Japan IDDM Network Research Grant . Appendix A
Publisher Copyright:
© 2019 The Authors
PY - 2020/1/22
Y1 - 2020/1/22
N2 - Viral infection is a putative causal factor for the development of type 1 diabetes, but the exact pathogenic mechanism of virus-induced diabetes (VID) remains unclear. Here, to identify the critical factors that regulate VID, we analyzed encephalomyocarditis D (EMC-D) VID-sensitive DBA/2 mice in comparison with resistant B6 mice. EMC-D virus-induced cell death occurred more frequently in DBA/2 β-cells than in B6 β-cells with 100U/ml IFN-β priming in vitro. We therefore purified β-cells using flow cytometry from mice two days after EMC-D virus infection and subjected them to microarray analysis. As a results, innate immune response pathway was found to be enriched in B6 β-cells. The signal transducer and activator of transcription 2 (Stat2) gene interacted with genes in the pathway. Stat2 gene expression levels were lower in DBA/2 mice than in B6 mice, restrictive to β-cells. Moreover, administration of IFN-β failed to upregulate Stat2 gene in DBA/2 β-cells than in those of B6 in vivo. The viral titer significantly increased only in the DBA/2 pancreas. Thus, these provided data suggest that impaired upregulation of Stat2 gene restrictive to β-cells at the early stage of infection is responsible for VID development in DBA/2 mice.
AB - Viral infection is a putative causal factor for the development of type 1 diabetes, but the exact pathogenic mechanism of virus-induced diabetes (VID) remains unclear. Here, to identify the critical factors that regulate VID, we analyzed encephalomyocarditis D (EMC-D) VID-sensitive DBA/2 mice in comparison with resistant B6 mice. EMC-D virus-induced cell death occurred more frequently in DBA/2 β-cells than in B6 β-cells with 100U/ml IFN-β priming in vitro. We therefore purified β-cells using flow cytometry from mice two days after EMC-D virus infection and subjected them to microarray analysis. As a results, innate immune response pathway was found to be enriched in B6 β-cells. The signal transducer and activator of transcription 2 (Stat2) gene interacted with genes in the pathway. Stat2 gene expression levels were lower in DBA/2 mice than in B6 mice, restrictive to β-cells. Moreover, administration of IFN-β failed to upregulate Stat2 gene in DBA/2 β-cells than in those of B6 in vivo. The viral titer significantly increased only in the DBA/2 pancreas. Thus, these provided data suggest that impaired upregulation of Stat2 gene restrictive to β-cells at the early stage of infection is responsible for VID development in DBA/2 mice.
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U2 - 10.1016/j.bbrc.2019.10.193
DO - 10.1016/j.bbrc.2019.10.193
M3 - Article
C2 - 31708097
AN - SCOPUS:85075424160
SN - 0006-291X
VL - 521
SP - 853
EP - 860
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -
