Suppression of SOCS3 expression in the pancreatic beta-cell leads to resistance to type 1 diabetes.
Type 1 diabetes results from the selective destruction of insulin-producing pancreatic beta-cells during islet inflammation, which involves inflammatory cytokines and free radicals. However, mechanisms for protecting beta-cells from destruction have not been clarified. In this study, we define the role of SOCS3 on beta-cell destruction using beta-cell-specific SOCS3-conditional knockout (cKO) mice. The beta-cell-specific SOCS3-deficient mice were resistant to the development of diabetes caused by streptozotocin (STZ), a genotoxic methylating agent, which has been used to trigger beta-cell destruction. The islets from cKO mice demonstrated hyperactivation of STAT3 and higher induction of Bcl-xL than did islets from WT mice, and SOCS3-deficient beta-cells were more resistant to apoptosis induced by STZ in vitro than were WT beta-cells. These results suggest that enhanced STAT3 signaling protects beta-cells from destruction induced by a genotoxic stress and that STAT3/SOCS3 can be a potential therapeutic target for the treatment of type 1 diabetes.
Mori
Hiroyuki
H
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Shichita
Takashi
T
Yu
Qingsheng
Q
Yoshida
Ryoko
R
Hashimoto
Masayuki
M
Okamoto
Fuyuki
F
Torisu
Takahiro
T
Nakaya
Mako
M
Kobayashi
Takashi
T
Takaesu
Giichi
G
Yoshimura
Akihiko
A
D000818:Animals; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D020868:Gene Silencing; D007113:Immunity, Innate; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013311:Streptozocin; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*
D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013311:Streptozocin