The use of glucocorticoids for treatment of sepsis has waxed and waned during the past several decades, and recent randomized controlled trials have evoked a reassessment of this therapy. Most glucocorticoid actions are mediated by its specific intracellular receptors (GRs). Thus we initially evaluated if sepsis and high-dose corticosteroid therapy can regulate guinea-pig pulmonary expression of GRs; active receptor, GR, and dominant negative receptor, GR. Sepsis induction by lipopolysaccharide (LPS) injection (300 µ/kg ip) decreased mRNA and protein levels of GR and increased protein expression of GR in lungs. High-dose methylprednisolone (40 mg/kg ip), administered simultaneously with LPS, markedly potentiated the decrease in GR expression but slightly affected the increase in GR expression. Consequently, this led to a significant reduction in GR nuclear translocation. Nevertheless, methylprednisolone treatment strongly eliminated LPS induction of NF-B activity, as determined by NF-B nuclear translocation and by gel mobility shift assays. Furthermore, the LPS-induced increase in inflammatory cells in bronchoalveolar lavage fluid was blunted by administration of the corticosteroid. On the other hand, immunofluorescent staining for cleaved caspase-3 showed a marked increase in this pro-apoptotic marker in lung sections, and transferase-mediated dUTP nick end labeling (TUNEL) represented an enhanced appearance of cell apoptosis in lungs and spleen, when methylprednisolone was given together with LPS. Cell apoptosis is now considered to play a role in the pathogenesis of the septic syndrome. We thus suggest that the action of glucocorticoids at high doses to accelerate sepsis-induced cell apoptosis may overwhelm their therapeutic advantages in septic shock.