Ras inhibition attenuates pancreatic cell death and experimental type 1 diabetes: possible role of regulatory T cells.
Regulatory T cells (Treg) play a crucial role in the maintenance of immune homeostasis and prevention of autoimmune diseases. Ras inhibition by 5-fluoro-farnesylthiosalicylic acid (F-FTS) was recently shown to increase the number and boost the suppressive function of Treg, thereby reducing the incidence of experimental diabetes in non-obese diabetic (NOD) mice. To investigate the effect of F-FTS on pancreatic beta cells and the possible involvement of Treg in such an effect, we evaluated the incidence of diabetes and assayed the pancreatic expression of Foxp3, cleaved caspase 3, and Ras-GTP expression in NOD mice treated with different doses of F-FTS. The treated mice showed attenuated progression of experimental diabetes, accompanied by an increase in serum insulin. Daily injections of F-FTS led to an increase in both the number and the migratory capacity of pancreatic Foxp3(+)CD4(+)CD25(+) Treg, while cleaved caspase 3 in the pancreas were significantly decreased, indicating reduced apoptosis. The Treg population induced by F-FTS helped to preserve pancreatic beta-cell viability in the presence of effector T cells. These findings suggest that inhibition of Ras by F-FTS in mice with experimental diabetes upregulates the Treg pool, which infiltrates the pancreas and attenuates the apoptotic cell death of beta cells. It thus appears that F-FTS induces Treg to play a protective role in the progression of experimental type-1 diabetes, suggesting that these cells represent a potential target for the treatment of this disorder.
Aizman
Elizabeta
E
Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel.
Mor
Adi
A
George
Jacob
J
Kloog
Yoel
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology*; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D018631:ras Proteins / Q000037:antagonists & inhibitors*
C553900:5-fluorofarnesylthiosalicylic acid; D001565:Benzoates; D007328:Insulin; D013438:Sulfhydryl Compounds; D018631:ras Proteins