Prevention of autoimmune diabetes by linomide in nonobese diabetic (NOD) mice is associated with up-regulation of the TCR-mediated activation of p21(ras).
Oral therapy with linomide protects prediabetic nonobese diabetic (NOD) mice from insulin-dependent diabetes mellitus. The mechanisms by which linomide exerts its protective effect are not fully understood. A decreased TCR-mediated activity of the GTP-GDP binding p21(ras) proto-oncogene is associated with prediabetes in NOD mice. However, the role of this signal transduction defect in the pathogenesis of autoimmune diabetes is not known. The TCR-mediated and protein kinase C-induced activations of p21(ras) were determined in mononuclear cells from lymph nodes of linomide-treated and untreated prediabetic NOD mice. TCR cross-linking by Con A induced an increase of 13 +/- 6.8% and a decrease of 0.8 +/- 1.8% in p21(ras) activity in the linomide-treated group and the untreated controls, respectively. Cell stimulation with PMA resulted in a 15 +/- 2% increase in p21(ras) activity in the linomide-treated mice and a 10 +/- 11.4% decrease in the untreated mice. Protein levels of p21(ras) and its regulatory elements, the GTPase-activating protein and the guanine nucleotide-releasing factor, mSOS, were comparable in both groups. We, therefore, conclude that prevention of autoimmune diabetes by linomide is associated with up-regulation of the p21(ras) T cell signal transduction defect in NOD mice.
Diabetes Unit, Assaf Harofeh Medical Center, Tel-Aviv University, Israel.
M J
MJ
Rapoport
L
L
Weiss
A
A
Mor
T
T
Bistritzer
Y
Y
Ramot
S
S
Slavin
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D005260:Female; D006912:Hydroxyquinolines / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis* / Q000187:drug effects; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*
D000276:Adjuvants, Immunologic; D006912:Hydroxyquinolines; D011948:Receptors, Antigen, T-Cell; C045282:roquinimex; D016283:Proto-Oncogene Proteins p21(ras)