INVOLVEMENT OF C-MYC IN THE RESISTANCE OF NONOBESE DIABETIC MICE TO GLUCOCORTICOID-INDUCED APOPTOSIS

Non-obese diabetic (NOD) mice spontaneously develop insulin-dependent diabetes mellitus (IDDM) as a consequence of autoimmune aggression of beta cells of the endocrine pancreas by T cells. T lymphocytes of NOD mice are resistant to apoptosis induced by glucocorticoids, or by star ving or DNA-damaging treatments, a feature that was interpreted as bei ng linked to escape of autoreactive T cells from thymic negative selec tion, c-myc is one of the gene targets of glucocorticoids (GC), its ex pression being down-regulated by the activated GC-GC receptor complex. We investigated here whether expression of Myc protein, in response t o dexamethasone stimulation, was the same in NOD mice and in non-autoi mmune strains, namely NON, BALB/c and C57B1.6. We found a consistent i ncrease in the levels of Myc protein after GC-treatment of lymphocytes of NOD mice, a finding that was in contrast to the down-regulation of c-myc that we observed in lymphocytes from mice not prone to diabetes . We also report that, rather than a absolute resistance to GC-induced cell death, NOD mice display a delayed apoptotic response to GC. We p ropose that the resistance of NOD mice lymphocytes to GC-induced apopt osis is because of inhibition of the repressive action of GC-GR comple xes at the level of c-myc transcription. This deficient action of GC-G R results in increased production of nuclear Myc protein, peculiar to NOD mice cells, following their treatment with GC.