Glucocorticoid action on the immune system.
Glucocorticoids have profound effects on immune function that are mediated, in part, by steroid-induced cell death. Our studies have been aimed at identifying the mechanism of this lymphocytolytic process using the rat thymocyte as a model system. Administration of glucocorticoids in vivo resulted in internucleosomal cleavage of the lymphocyte genome that was detectable within 2 h of treatment and increased with time after hormone administration. Six h after steroid treatment greater than 50% of the genome was degraded, yet cell viability remained greater than 90% indicating that this event preceded cell death. Furthermore, this process appeared to be mediated by the glucocorticoid receptor since the antagonist RU 486 blocked glucocorticoid-mediated DNA degradation. To further characterize this lymphocytolysis we have analyzed glucocorticoid-treated thymocytes for nucleases. Two families of nuclear proteins have been identified, a 30-32 kDa doublet and a series of 3-4 proteins that are 12-19 kDa, both of which are induced by glucocorticoid treatment (137 +/- 6% and 342 +/- 24%, respectively) and have prominent nuclease activity. These nucleases can also be induced in vitro indicating that glucocorticoids act directly on thymocytes to mediate this response. Moreover, this nuclease induction, like glucocorticoid-mediated DNA degradation, could be blocked by RU 486. Based on these findings we propose a working model of glucocorticoid-mediated lymphocytolysis in which these steroids, acting via a receptor mediated process, induce the expression of a lysis gene product (nuclease) which degrades the genome and results in cell death.
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D003851:Deoxyribonucleases / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D004963:Estrenes / Q000494:pharmacology; D015735:Mifepristone; D008954:Models, Biological; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects*
D004963:Estrenes; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone; D004247:DNA; D003851:Deoxyribonucleases