Induction of thymocyte apoptosis by systemic administration of concanavalin A in mice: role of TNF-alpha, IFN-gamma and glucocorticoids.
Administration of concanavalin A (Con A) is a well-established model of acute immune-mediated hepatitis. Here, we demonstrate that intravenous injection of Con A in mice induces profound thymic atrophy. Compared to liver damage, the kinetics of Con A-induced thymic atrophy is slower and more prolonged; the nadir in thymocyte number is reached 4 days after Con A injection, whereas peak transaminase levels are observed at 12-24 h. Marked alterations in the ratio of CD4+ and CD8+cells in the thymus and spleen and significantly increased rates of thymocyte and splenocyte apoptosis are observed. Neutralization of the cytokines TNF-alpha or IFN-gamma, which protects mice from Con A-induced hepatitis, prevents thymic atrophy as well as alterations in CD4+ and CD8+ cell numbers and apoptosis rates. However, neither TNF-alpha nor IFN-gamma are detectable in thymocyte lysates after Con A injection, whereas both cytokines are present in liver, spleen and serum. Administration of the glucocorticoid receptor antagonist mifepristone does not prevent thymic atrophy, thus ruling out a possible contribution of endogenous glucocorticoids. Con A-induced thymic atrophy is accompanied by down-regulation of Bcl-2 expression in the thymus, which is prevented by neutralization of TNF-alpha or IFN-gamma. These data demonstrate that the thymus is a critical target organ of Con A-induced inflammation; the effects of Con A on the thymus are mediated by extrathymic production of TNF-alpha and IFN-gamma, but not by glucocorticoids.
Fayad
Raja
R
Department of Human Nutrition, University of Illinois at Chicago, Chicago, IL 60612, USA.
Sennello
Joseph A
JA
Kim
Soo-Hyun
SH
Pini
Maria
M
Dinarello
Charles A
CA
Fantuzzi
Giamila
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D003208:Concanavalin A / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D005938:Glucocorticoids / Q000502:physiology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000502:physiology*; D008099:Liver / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
D015704:CD4 Antigens; D016827:CD8 Antigens; D005938:Glucocorticoids; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D007371:Interferon-gamma