Heme oxygenase-1 (HO-1), an enzyme important in protection against oxidant stress, is induced in human vascular endothelial cells by the cytokines tumor necrosis factor- (TNF-) and interleukin-1 (IL-1). However, the signaling mediators that regulate the induction are not known. This study examined the involvement of protein kinase C (PKC), phospholipase A₂ (PLA₂), calcium, and oxidants in cytokine induction of HO-1. Acute exposure to the PKC activator phorbol 12-myristate 13-acetate (PMA) stimulated HO-1 mRNA. However, prolonged exposure, which downregulates most PKC isoforms, blocked induction of HO-1 mRNA by IL-1 and TNF-. Additionally, the phosphatase inhibitors okadaic acid and calyculin enhanced cytokine induction of HO-1. Mepacrine, a PLA₂ inhibitor, prevented HO-1 induction by cytokine, suggesting a role for arachidonate, the product of PLA₂ hydrolysis of phospholipids, in HO-1 expression. The intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) blocked cytokine induction of HO-1. Paradoxically, the calcium ionophore A-23187 prevented HO-1 induction by cytokine but not by PMA. Finally, the oxidant scavenger N-acetylcysteine inhibited HO-1 induction by cytokines. These results demonstrate that TNF- and IL-1 induction of HO-1 requires PKC-mediated phosphorylation and PLA₂ activation as well as oxidant generation.

cytokine; phorbol 12-myristate 13-acetate; phosphatase; protein kinase C downregulation; protein kinase C isoforms; tumor necrosis factor-; interleukin-1

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