The present study investigates the involvement of heme oxygenase-1 (HO-1) and ferritin in mediating cytoprotective and antioxidant actions of prostaglandins. The prostaglandin derivates PGE1, iloprost and d-PGJ2, in contrast to PGF2α, led to an increased expression of HO-1 protein in endothelial cells and macrophages in a concentration and time-dependent manner. Furthermore, PGE1 caused an increase in ferritin protein expression. These findings could also be verified at the transcriptional level through gene reporter assays. PGE1-induced HO-1 protein expression was accompanied by an increased catalytic activity of the enzyme. PGE1 also reduced NADPH-dependent production of reactive oxygen species at concentrations which were effective in HO-1 induction. In subsequent experiments the underlying mechanisms of PGE1-mediated HO-1 induction were investigated. As adenosine 3´-5´-cyclic monophosphate (cAMP) is an important intracellular signaling molecule in mediating prostaglandin effects, we examined intracellular levels of cAMP. PGE1 and iloprost increased intracellular cAMP levels in a concentration-dependent manner. In contrast, d-PGJ2 and PGF2α did not alter cAMP concentration. To determine whether PGE1-dependent induction of HO-1 was regulated via the cAMP pathway, cell cultures were preincubated with different selective inhibitors. Inhibition of adenylate cyclase or protein kinase A using DDA and KT5720 efficiently inhibited PGE1-induced HO-1 expression. By using luciferase promotor constructs and mutational analysis, it was demonstrated that a cAMP-responsive element (CRE) is responsible for the induction of HO-1 transcription by PGE1. These findings show that PGE1 is a novel, potent activator of the HO-1/ferritin system through a cAMP-dependent cascade. Activation of the HO-1 gene via PGE1 may clinically translate into an antioxidant protection of vascular and non-vascular tissue and thus prevent atherogenesis as well as other inflammatory or autoimmune processes.