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.
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.
Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines, Rd, La Jolla, CA 92037, USA.
Michelle
M
Solomon
Malin
M
Flodström-Tullberg
Nora
N
Sarvetnick
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000628:therapy; D015536:Down-Regulation / Q000187:drug effects; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control; D050417:Insulin-Secreting Cells / Q000378:metabolism; D050856:Interferon Regulatory Factor-1 / Q000235:genetics* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D050856:Interferon Regulatory Factor-1; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma