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Lymphocyte Cell Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
Glucocorticoids are widely used in the therapy of
inflammatory, autoimmune, and allergic diseases. As the end-effectors
of the hypothalamic-pituitary-adrenal axis, endogenous glucocorticoids
also play an important role in suppressing innate and cellular immune
responses. Previous studies have indicated that glucocorticoids inhibit
Th1 and enhance Th2 cytokine secretion. IL-12 promotes Th1
cell-mediated immunity, while IL-4 stimulates Th2 humoral-mediated
immunity. Here, we examined the regulatory effect of glucocorticoids on
key elements of IL-12 and IL-4 signaling. We first investigated the
effect of dexamethasone on IL-12-inducible genes and showed that
dexamethasone inhibited IL-12-induced IFN-
secretion and IFN
regulatory factor-1 expression in both NK and T cells. This occurred
even though the level of expression of IL-12 receptors and
IL-12-induced Janus kinase phosphorylation remained unaltered. However,
dexamethasone markedly inhibited IL-12-induced phosphorylation of Stat4
without altering its expression. This was specific, as IL-4-induced
Stat6 phosphorylation was not affected, and mediated by the
glucocorticoid receptor, as it was antagonized by the glucocorticoid
receptor antagonist RU486. Moreover, transfection experiments showed
that dexamethasone reduced responsiveness to IL-12 through the
inhibition of Stat4-dependent IFN regulatory factor-1 promoter
activity. We conclude that blocking IL-12-induced Stat4
phosphorylation, without altering IL-4-induced Stat6 phosphorylation,
appears to be a new suppressive action of glucocorticoids on the Th1
cellular immune response and may help explain the
glucocorticoid-induced shift toward the Th2 humoral immune
response.
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