Proinflammatory cytokines have been shown to influence the ex- pression and function 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-1a (IL-1a), on 1) GR translocation from cytoplasm to nucleus using GR immunostaining, 2) cytosolic radioligand GR bind- ing, and 3) GR-mediated gene transcription in L929 cells stably trans- fected with the mouse mammary tumor virus-cholamphenicol acetyl- transferase reporter gene. L929 cells were treated with IL-1a (100 and 1000 U/ml) for 24 h in the presence or absence of dexamethasone (Dex; 10 nM to 1 mM). IL-1a inhibited Dex-induced GR translocation and alone induced GR up-regulation. Pretreatment with IL-1a followed by Dex treatment for 1.5 h led to about 20% inhibition of Dex-induced GR-mediated gene transcription, whereas coincubation of IL-1a plus Dex for 24 h inhibited Dex-induced GR-mediated gene activity up to 42%. The latter effect was reversed by the IL-1 receptor antagonist. These results suggest that cytokines produced during an inflamma- tory response may induce GR resistance in relevant cell types by direct effects on the GR, thereby providing an additional pathway by which the immune system can influence the hypothalamic-pituitary- adrenal axis. (Endocrinology 140: 4359 - 4366, 1999)