Glucocorticoids and immune responses

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Abstract
We describe a series of investigations on mechanisms of antiinflammatory and immunosuppressive actions of glucocorticoids. Glucocorticoid receptors and primary mechanisms of action have been studied with isolated rat thymus cells. When added to these cells glucocorticoids immediately form cytoplasmic hormone‐receptor complexes which after activation bind to the nuclei where they apparently induce mRNA for specific proteins that rapidly inhibit glucose transport and acetate incorporation into lipids. Protein and RNA metabolism are inhibited more slowly and eventually the cells die. With normal peripheral human lymphocytes, similar but slower effects are produced. A dramatic increase in receptor sites per cell is seen in lymphocytes stimulated with concanavalin A or antigen. This increase is probably associated with preparation for mitosis. We do not find, contrary to widespread belief, that these stimulated cells are insensitive to glucocorticoids. Such insensitivity has been invoked to explain the insensitivity to glucocorticoid suppression of secondary compared to primary immune responses. An alternative explanation emerges from our experiments with T‐cell growth factor. T‐cell growth factor, produced by mitogen or antigen stimulated spleen cells, is necessary for the proliferation of T‐lymphocytes in culture and may be responsible for clonal expansion of antigen‐responsive T‐cells. Treatment of Con A‐stimulated rat spleen cells or human peripheral mononuclear cells with 100 nMdexamethasone inhibits the production of the growth factor by 95%. This effect is specific for glucocorticoids. Addition of T‐cell growth factor completely reverses the inhibition by glucocorticoid of mitogen‐induced blastogenesis. We propose that the inhibitory actions of glucocorticoids on antigen‐ or mitogen‐induced T‐cell blastogenesis are related to inhibition of production of T‐cell growth factor and that the reason the primary immune response is more sensitive to glucocorticoids is that by inhibiting production of T‐cell growth factor, glucocorticoids block the clonal expansion necessary to amplify the primary response. We have also studied effects of glucocorticoids on Fc receptors, which play important roles in phagocytosis and other aspects of immune responses. Treatment of the human progranulocytic cell line HL‐60 with dexamethasone for 72 hours reduces by 35‐50% the Fc receptors per cell with no effect on cell viability or proliferation and slight increase in leucine incorporation. The effect is specific for glucocorticoids. These findings indicate that an important component in glucocorticoid‐induced immunosuppression may be a reduction in Fc receptors, and with the results on T‐cell growth factor, suggest that glucocorticoids regulate immune processes via effects on lymphokines and other immunologically important proteins.