Background Our previous studies showed the increased leukotriene B4 (LTB4) level in brain may have negative feedback regulatory effects through an increase in systemic glucocorticoids during an asthmatic attack in rats.Glucocorticoids act on peripheral target tissues to restore homeostasis to the organism and engage glucocorticoid receptors (GR) in the CNS to control the intensity and duration of the stress response.However, GR expression and its functional role in the brain under normal conditions or in neuroinflammatory processes remain unclear.The present study further investigated the GR expression in the hypothalamic-pituitary-adrenal (HPA) axis induced by LTB4 in regulating antigen-induced asthmatic response in sensitized rats and explored the underlying mechanisms.Methods In vivo studies, ovalbumin (OVA)-sensitized rats were challenged by inhalation of antigen.LTB4 and U75302 (a selective LTB4 BLT1 receptor inhibitor) or LY255283 (a selective LTB4 BLT2 receptor inhibitor) were administered via hypothalamic injection 30 min before challenge.In vitro studies, we employed a hypothalamic organ culture system which enabled us to evaluate GR expression from individually incubated hemihypothalami explanted from rats.Inhibitors were used to block the mitogen-activated protein kinase (MAPK) and NF-κ B pathways to examine the mechanism in PC12 cells.Expression of GR mRNA and protein in HPA axis were evaluated by RT-PCR, Q-PCR and Western Blot.Results Both in vitro and in vivo studies, expression of GR in hypothalamus, pituitary and adrenal were up-regulated by LTB4 (30 ng· mL-1) both in nomal and asthmatic rats.These effects were completely blocked by pre-treatment with BLT1 receptor antagonist U75302 (100 ng),and partly inhibited by BLT2 receptor antagonist LY255283 (100 ng).LTB4-mediated expression of GR was accompanied by activation of Erk1/2, JNK and P38 MAPK, whereas it did not affect the phosphorylation of AKT and STAT3.LTB4-induced GR protein upregulation was effectively suppressed by the selective P38 inhibitor.Conclusions and general significance Taken together, these data indicate that LTB4 induced upregulation of GR mRNA and protein expression in the HPA axis through activation of MAPK signal pathway via its BLT1 receptor.Our results indicate that stress response is characterized by increased central inflammation and concomitant HPA axis activation, most likely having a role in protection of the organism from overwhelming inflammatory reaction.