TY - JOUR
T1 - Beta-cell specific expression of suppressor of cytokine signaling-1 (SOCS-1) delays islet allograft rejection by down-regulating Interferon Regulatory Factor-1 (IRF-1) signaling
AU - Solomon, Michelle
AU - Flodström-Tullberg, Malin
AU - Sarvetnick, Nora
N1 - Funding Information:
We gratefully acknowledge Daisy Dietz, Patrick Secrest, Alex Stotland, Mary Cleary and Leah Varney for their technical assistance. We would also like to thank Marcie Kritzik for her help in writing and preparing this manuscript. The manuscript was supported by a grant from the NIH, #AI050864. M. Solomon was supported by a fellowship from the Juvenile Diabetes Research Foundation #3-2004-174. M. Flodström-Tullberg was supported by the Juvenile Diabetes Research Foundation (#10-2001-818), the Swedish Foundation for Strategic Research, the Swedish Research Council, Åke Wiberg and Jeansson's Foundations. This is manuscript number 17625-IMM from The Scripps Research Institute.
PY - 2011/4/15
Y1 - 2011/4/15
N2 - We previously showed that targeted expression of SOCS-1 (Suppressor of Cytokine Signaling-1) to pancreatic beta cells (SOCS-1-transgenic (Tg) islets) from C57BL6/J mice delays islet allograft rejection in BALB/c mice. In the present study, we extend these observations to investigate the mechanism of this delayed rejection. We found that transgene expression of SOCS-1 rendered the islets significantly more resistant to cytokine-induced cell death after treatment with TNF-alpha alone and in combination with IFN-gamma. Furthermore, protection against cytokine-induced cytotoxicity correlated with significant inhibition of the transcription factor interferon regulatory factor-1 (IRF-1), reflecting enhanced cell survival signals. Moreover, we found that IFNg-induced class I MHC upregulation was significantly impaired in SOCS-1-Tg islets compared to non-Tg islets in the BALB/c host. Importantly, SOCS-1-Tg islets were able to reverse streptozotocin-induced diabetes for at least 2. weeks longer than normal islets. Our findings indicate that intra-graft expression of SOCS-1 renders islets insensitive to the deleterious effects of cytokines; this finding could be important in the development of therapies against acute allograft rejection.
AB - We previously showed that targeted expression of SOCS-1 (Suppressor of Cytokine Signaling-1) to pancreatic beta cells (SOCS-1-transgenic (Tg) islets) from C57BL6/J mice delays islet allograft rejection in BALB/c mice. In the present study, we extend these observations to investigate the mechanism of this delayed rejection. We found that transgene expression of SOCS-1 rendered the islets significantly more resistant to cytokine-induced cell death after treatment with TNF-alpha alone and in combination with IFN-gamma. Furthermore, protection against cytokine-induced cytotoxicity correlated with significant inhibition of the transcription factor interferon regulatory factor-1 (IRF-1), reflecting enhanced cell survival signals. Moreover, we found that IFNg-induced class I MHC upregulation was significantly impaired in SOCS-1-Tg islets compared to non-Tg islets in the BALB/c host. Importantly, SOCS-1-Tg islets were able to reverse streptozotocin-induced diabetes for at least 2. weeks longer than normal islets. Our findings indicate that intra-graft expression of SOCS-1 renders islets insensitive to the deleterious effects of cytokines; this finding could be important in the development of therapies against acute allograft rejection.
KW - Cytokines
KW - Cytotoxicity
KW - Diabetes
KW - MHC
KW - Transplantation
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U2 - 10.1016/j.trim.2010.11.007
DO - 10.1016/j.trim.2010.11.007
M3 - Article
C2 - 21130166
AN - SCOPUS:79951518123
VL - 24
SP - 181
EP - 188
JO - Transplant Immunology
JF - Transplant Immunology
SN - 0966-3274
IS - 3
ER -