The proinflammatory cytokine, interleukin-1 alpha, reduces glucocorticoid receptor translocation and function

Proinflammatory cytokines have been shown to influence the expression and f unction of the glucocorticoid receptor (GR). Specifically, several studies have found that cytokines induce a decrease in GR function, as evidenced by reduced sensitivity to glucocorticoid effects on functional end points. To investigate the potential mechanism(s) involved, we examined the impact of the proinflammatory cytokine, interleukin-1 alpha (IL-1 alpha), on 1) GR t ranslocation from cytoplasm to nucleus using GR immunostaining, 2) cytosoli c radioligand GR binding, and 3) GR-mediated gene transcription in L929 cel ls stably transfected with the mouse mammary tumor virus-cholamphenicol ace tyltransferase reporter gene. L929 cells were treated with IL-1 alpha (100 and 1000 U/ml) for 24 h in the presence or absence of dexamethasone (Dex; 1 0 nM to 1 mu M). IL-1 alpha inhibited Dex-induced GR translocation and alon e induced GR up-regulation. Pretreatment with IL-1 alpha followed by Dex tr eatment for 1.5 h led to about 20% inhibition of Dex-induced GR-mediated ge ne transcription, whereas coincubation of IL-1 alpha plus Dex for 24 h inhi bited Dex-induced GR-mediated gene activity up to 42%. The latter effect wa s reversed by the IL-1 receptor antagonist. These results suggest that cyto kines produced during an inflammatory response may induce GR resistance in relevant cell types by direct effects on the GR, thereby providing an addit ional pathway by which the immune system can influence the hypothalamic-pit uitary-adrenal axis.