Increased sensitivity of glioblastoma cells to interleukin 1 after long-term incubation with dexamethasone

Cytokines may act as chemical messengers in the central nervous system and affect trophic, immune, and neuroendocrine functions. However, little is known about the regulation of cytokine production in nervous system tissue, although it has been demonstrated recently that glucocorticoids augment interleukin 1 (IL 1) receptor expression in the glioblastoma cell line, U87MG. Here, the effects of glucocorticoids on IL 1-induced interleukin 6 (IL 6) production are determined in the same cell line. During short-term incubations of U87MG cells (6 h) in the presence of IL 1beta and dexamethasone (DEX), DEX inhibited IL 1beta-stimulated IL 6 production over the entire range of the dose-response curve. However, when cells were preincubated in the presence of DEX for 15 h and then challenged with IL 1beta or IL 1beta and DEX, there was a left-shift in the IL 1,B dose-response curve, suggesting an increased sensitivity of the cells to respond to IL 1 and produce IL 6. In fact, the ED(50) for IL 1beta-stimulated IL 6 production was about 1.3 pM in cells not preincubated with DEX, but was reduced to 0.25 pM in cells that were preincubated with DEX. However, maximum IL 6 production at high doses of IL 1beta was inhibited in cells cultured in the presence of DEX during the IL 1 challenge. Thus, the results suggest the possibility that when glucocorticoids are elevated for extended periods, and concentrations of IL 1 are low because of steroid suppression of IL 1 production, actions of IL 1 may be maintained or even augmented due to up-regulated IL 1 receptor expression in particular cell types. This would allow for glucocorticoid-targeted actions of IL-1 to be maintained in particular cell types that up-regulate IL 1 receptors in response to glucocorticoid, whereas in those cell types that do not up-regulate IL 1 receptor number, IL 1 actions are suppressed.