Methylprednisolone and 2-chloroadenosine induce DNA fragmentation at different stages of human T-lymphocyte development.
Both methylprednisolone (MPS) and 2-chloroadenosine (2-CA) were shown previously to induce DNA fragmentation and cell death in human thymocytes at an optimum concentration of 1 and 40 microM, respectively. Though both compounds affected the CD4+CD8+ population, 2-CA depleted primarily thymocytes expressing medium or high levels of CD3-T-cell receptor molecule, while the glucocorticoid treatment affected cells expressing a lower level of CD3-T-cell receptor. Their effect on thymocyte viability and DNA fragmentation was observed already at day 1 of culture and involved the bcl-2 negative thymocytes. Incubation of peripheral T-lymphocytes (which express bcl-2) with the same concentration of MPS did not affect the viability for up to 5 days, while 2-CA induced 100% cell death and DNA fragmentation by day 5. If T-cells were stimulated with concanavalin A in the presence of MPS or 2-CA the cell proliferation was inhibited and a decrease in cell viability with a concomittant increase in DNA fragmentation was observed. If MPS was added at 24 h or later after mitogenic stimulation, it was not able to induce apoptosis and the inhibition of proliferation was less pronounced. 2-CA, on the other hand, inhibited proliferation and induced cell death whenever it was added to the culture. The decreased sensitivity towards the apoptosis induction effects of glucocorticoids at later phases of mitogenic stimulation can not be explained by an increased bcl-2 expression, since its expression level remained constant up to 48 h after mitogenic stimulation. Our data presented in this paper suggest: (1) that T-cells may show different sensitivity towards the same apoptosis inducer signals at different stages of the T-cell development; (2) the apoptotic sensitivity towards various signals may be different at the same stage of T-cell differentiation; and (3) their apoptotic sensitivity does not always correlate with the bcl-2 expression alone.
Szondy
Z
Z
Department of Biochemistry, University Medical School of Debrecen, Hungary. szondy@indi.dote.hu
D015762:2-Chloroadenosine / Q000494:pharmacology*; D017209:Apoptosis; D002455:Cell Division; D017637:Clonal Deletion; D004249:DNA Damage; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007223:Infant; D008775:Methylprednisolone / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D013950:Thymus Gland / Q000166:cytology; D013997:Time Factors
D005938:Glucocorticoids; D019253:Proto-Oncogene Proteins c-bcl-2; D015762:2-Chloroadenosine; D008775:Methylprednisolone