Sex difference in resistance to dexamethasone-induced apoptosis in NOD mice: treatment with 1,25(OH)2D3 restores defect.
The NOD mouse, a model for type 1 diabetes, is characterized by resistance to apoptosis in immunocytes. The aim of this study was to investigate a link between apoptosis in NOD thymocytes and autoimmunity. First, we demonstrated that the sexual dimorphism in diabetes incidence in NOD mice (females are more diabetes-prone than males) is reflected by differences in apoptosis. Apoptosis in NOD thymocytes, 24 h after dexamethasone, was decreased in both sexes compared with C57B1/6, but it was lower in female mice (26 +/- 2%) than in male mice (50 +/- 3%, P < 0.001). Further, we demonstrated that sex hormones themselves play a central role in this difference, since castration of NOD male mice, which increases diabetes incidence, decreased apoptosis levels (32 +/- 2%), while treatment of NOD female mice with dihydrotestosterone, which protects against diabetes, restored apoptosis to male levels (42 +/- 1.5%). Finally, we demonstrated that 1,25-dihydroxyvitamin D3, a steroid hormone that prevents diabetes in NOD mice, restored apoptosis levels to C57B1/6 reference levels. This improved apoptosis was seen in male (68 +/- 1 vs. 50 +/- 3% in untreated NOD mice, P < 0.001) but especially in female NOD mice (51 +/- 5 vs. 26 +/- 2% in untreated NOD mice, P < 0.001). Fluorescence-activated cell sorter analysis of thymocyte subsets revealed marked differences, especially in CD4+CD8+ and CD4+ cells. We conclude that the sexual dimorphism in diabetes incidence in NOD mice is paralleled by a dimorphism in resistance to apoptotic signals in NOD thymocytes. This resistance to apoptosis is driven by sex hormones and is corrected by 1,25-dihydroxyvitamin D3.
Casteels
K M
KM
Laboratory for Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Gasthiusberg, Belgium.
Gysemans
C A
CA
Waer
M
M
Bouillon
R
R
Laureys
J M
JM
Depovere
J
J
Mathieu
C
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015551:Autoimmunity; D002117:Calcitriol / Q000494:pharmacology* / Q000627:therapeutic use; D003907:Dexamethasone / Q000494:pharmacology* / Q000627:therapeutic use; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D013196:Dihydrotestosterone / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009919:Orchiectomy; D012727:Sex Characteristics; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology*
D005938:Glucocorticoids; D013196:Dihydrotestosterone; D003907:Dexamethasone; D002117:Calcitriol