Glucocorticoid receptors and their functions in lymphocytes

Abstract

Most, if not all. the effects of glucocorticoid hormones on lymphoid tissue are thought to be mediated by an initial step of interaction of the steroid with specific cytoplasmic receptors. We have presented results, obtained using whole cell suspensions of mouse thymocytes. showing however that the number of receptors does not accurately reflect the steroid sensitivity of the target cell: both inhibitory effects of steroid on nucleic acid precursor incorporation and steroid-induced cell lysis are not obligatorily related to receptor levels but more likely to cell differentiation. We have therefore also investigated the mechanism of the immunosuppressive effects of steroids and the role of various factors which could be involved in the proliferation or lysis of mouse thymocytes. Dexamethasone and 25-OH cholesterol are the most potent agents, capable of inhibiting cholesterol biosynthesis in non stimulated thymocytes. Although the effect of dexamethasone. which is blocked by actinomycin D. appears to be mediated through receptor occupancy, the action of 25-OH cholesterol is likely to be due to an inhibition of HMG COA reductase activity. Mitogen induced lymphoblastic transformation of thymocytes is blocked by low concentration of dexamethasone but also by sex steroids at higher concentrations. These compounds, which exert immunosuppressive effects in vivo, inhibit concanavalin A induced transformation at concentrations above 10 −5 M, at which concentration they also elicit a rapid and transient decrease of uridine uptake in non stimulated thymocytes. In addition, calcium, which has been considered to play an important role in the mechanism of steroid-induced lysis, appears highly toxic by itself.