Effects of lipopolysaccharide and chlorpromazine on glucocorticoid receptor-mediated gene transcription and immunoreactivity: a possible involvement of p38-MAP kinase

It has been hypothesized that dysregulations of the immune system and glucocorticoid receptor (GR) function are involved in the pathogenesis of schizophrenic disorders. Previously, we found that among antipsychotics, chlorpromazine most potently inhibited GR function under in vitro conditions. In order to study a role of the some immune system mediators in this process, we investigated the effect of lipopolysaccharide (LPS) on chlorpromazine-induced changes in GR-mediated gene transcription in fibroblast cells, stably transfected with mouse mammary tumor virus promoter (LMCAT cells). Two days of incubation of the cells with LPS (1 and 5 mug/ml) and chlorpromazine (3-30 muM) inhibited the corticosterone-induced gene transcription in a concentration-dependent manner. Concomitant incubation of the cells with LPS (1 mug/ml) and chlorpromazine had stronger inhibitory effect than that evoked by each compound alone. The effect of LPS, but not that of chlorpromazine, on GR function was dependent on p38 mitogen-activated protein kinase (MAPK). Moreover, LPS-stimulated proliferative activity was also p38-MAP kinase dependent, but this effect was suppressed by chlorpromazine. (C) 2004 Elsevier B.V. and ECNP. All rights reserved.