Interleukin 1 alpha (IL-1 alpha) induced activation of p38 mitogen-activated protein kinase inhibits glucocorticoid receptor function

Previous studies have demonstrated that interleukinalpha (IL-1alpha) inhibits glucocorticoid receptor (GR) nuclear translocation and dexamethasone (Dex)-induced gene transcription. Given that IL-1alpha is a potent activator of the p38 mitogen-activated protein kinase (MAPK) signal transduction pathway and p38 MAPK has been associated with reduced GR function, we examined the role of p38 MAPK in IL-1alpha-mediated inhibition of GR function in mouse fibroblast cells stably transfected with a GR-mediated reporter gene construct (LMCAT cells). Treatment of LMCAT cells with IL-1alpha (1000 U/ml) for 24 h inhibited Dex (50 nM)-induced GRE-CAT activity by similar to35%. When cells were cotreated for 24 h with IL-1alpha plus SB-203580 (0.5-1 muM), a selective p38 inhibitor, IL-1alpha's inhibitory effect on GR function as determined by Dex-induced GRE-CAT activity was reversed. Using gel mobility shift assay, SB-203580 was also found to reverse IL-1alpha inhibition of GR-GRE binding. Further confirming the role of p38 pathways, pretreatment of LMCAT cells with antisense oligonucleotides targeted to p38 MAPK completely abrogated IL-1alpha inhibition of Dex-induced GRE-CAT activity. Taken together, these results demonstrate that activation of p38 MAPK pathways are involved in IL-1alpha-mediated inhibition of GR function. In addition, these findings extend the intracellular targets of p38 to include the GR and indicate that p38 inhibitors may have special utility in immunologic and/or neuropsychiatric disorders associated with impaired GR-mediated feedback inhibition.