Monographs on endocrinology最新文献

A variety of human leukopathic diseases including human acute lymphoblastic leukemia are responsive to glucocorticoids in a varying proportion of cases. We identified specific glucocorticoid receptors in human acute lymphoblastic leukemia cells. Their presence or absence was well correlated with both in vivo and in vitro responsiveness of these target cells to glucocorticoids. These data suggest that knowledge of glucocorticoid receptor status in human acute lymphoblastic leukemia may aid in selecting patients for therapy. Furthermore, these receptors exhibit significant quantitative differences in various subtypes of human leukemia, with null-cell lymphoblastic leukemia having approximately three times the mean number of receptors per cell as T-cell leukemias. These differences in receptor levels are associated with major differences in complete remission duration independent of other prognosticators of response such as patient age, white count, and cell surface markers. Specific receptors for glucocorticoids can also be identified in normal human peripheral blood monocyte fractions including unpurified peripheral blood lymphocytes, T, and non-T subcomponents of circulating lymphocytes and circulating monocytes. By criteria of quantity, of binding affinity, and specificity, these receptors appear to be similar to other classical glucocorticoid receptors. Receptors in human peripheral blood lymphocytes may be induced threefold on a per cell basis by treatment with the mitogen phytohemagglutinin. This is associated with a marked increase in glucocorticoid responsiveness.

After reviewing briefly our earlier studies on glucocorticoid receptors and mechanisms in thymus cells, we have outlined results from the following two areas of current interest in our laboratories: the "life-cycle" of glucocorticoid receptors and complexes in thymus cells, and the levels of glucocorticoid receptors and sensitivity in immunologically stimulated human peripheral lymphocytes. Several of our results on energetics and kinetics of hormone binding to glucocorticoid receptors in rat thymus cells seem to require extension of the simplest model of hormone-receptor transformations in intact cells. ATP-depletion experiments suggest the existence of a nonbinding form of the receptor; "chase" experiments suggest reaction of hormone directly with nuclear-bound receptor; experiments on depletion and replenishment of cytoplasmic receptor using cortisol and dexamethasone suggest the existence of at least two subpopulations of nuclear-bound hormone-receptor complex. We have found that mitogen or immunologic stimulation of human peripheral lymphocytes in culture leads within 24 h or so to a striking increase in the number of glucocorticoid receptor sites per cell. We believe this increase may be due to partial synchronization of the cell population in a phase of the cell cycle in which receptor content is high. Contrary to the widely held view that mitogen-stimulated cells become insensitive to glucocorticoids, our experiments show that with respect to inhibition of thymidine and uridine incorporation and glucose uptake, the cells are highly sensitive to dexamethasone at 24, 48, and 72 h after stimulation with concanavalin A.

Several laboratories have documented that glucocorticoid hormones markedly stimulate the expression of mouse mammary tumor virus genes in a variety of mouse mammary tumor cells and in infected heterologous cells. The effect of the hormone appears to be a rapid and specific augmentation of the synthesis of viral RNA, mediated by interaction with glucocorticoid receptor proteins. The availability of virus-specific reagents and recent developments in the molecular biology of RNA tumor viruses now permit a highly refined analysis of hormonal regulation in this experimental system.

The spectrum of physiological, pathological, and genetic variations in sensitivity to glucocorticoids is reviewed. The receptor for these hormones is common to most mammalian tissues, and yet the responses are widely divergent. Although there may be differences in the receptors to account for some of this diversity, it is likely that it is largely due to cellular programming not involving the receptors. In addition to the intertissue differences in sensitivity, it is also clear that intra-tissue differences occur. The greatest amount of information has been accumulated with lymphoid cell systems and there are sensitivity differences to specific responses such as cell killing or effects on immunological functions. In these systems, there can be major variations in either the extent of the response (e. g., from mild growth inhibition to cellular killing) or whether any effect is observed. Further, dose requirements for certain responses can vary by several orders of magnitude. Within a given tissue there may be developmental changes in sensitivity that are not due to obvious changes in the receptor, and decreased sensitivity with aging that in some cases has been associated with changes in receptor binding activity. Finally, the cellular sensitivity can either be influenced by hormones and other factors that affect the ability of the glucocorticoid to elicit a particular response (in a synergistic or antagonistic manner), or the same function regulated by the glucocorticoid can be inducible by the steroid, appearing some time after administration of the steroid and disappearing after steroid removal. Genetic variations in sensitivity to glucocorticoids also occur. In humans these may be generalized, affecting glucocorticoid action in all responsive tissues, and could be important in the pathogenesis of certain diseases. Perhaps the most striking genetic alterations, however, are observed in cultured lymphoid and fibroblastic cells and in acute lymphoblastic leukaemia cells ordinarily growth inhibited or killed by the glucocorticoid. Mutant cell lines arise that are highly resistant and most of these have abnormalities in the glucocorticoid receptor. In some cases binding activity is totally lost, easily expalining the resistance. In other cases, there is a more modest reduction in binding or a change in receptor properties that give it increased or decreased nuclear and DNA binding activity. An analysis of these cell lines suggests that many of the defects are in some receptor property presently not understood that makes the receptor ineffective rather than the defect being due to the quantitative changes in receptor levels detected. The frequency of emergence of steroid-resistant cells can vary widely from about 10(-5) in S49 cells to less than 10(-8) in certain thymic cell lines...