Cytosolic phospholipase A(2)alpha (cPLA(2)alpha) catalyzes the hydrolysis of glycerophospholipids at the sn-2 position to liberate fatty acids. Although cPLA(2)alpha has been implicated in various cellular processes, the detailed mechanism of its expression remains to be elucidated. Here we report that phorbol 12-myristate 13-acetate (PMA) Up-regulates cPLA(2)alpha in A549 airway epithelium cells, and that this effect is sensitive to rottlerin, a potent inhibitor of protein kinase Cdelta (PKCdelta). Consistent with this observation, a dominant negative mutant of PKCdelta reduced cPLA(2)alpha induction in response to PMA. Up-regulation of cPLA(2)alpha by PMA was also inhibited by PDTC, an inhibitor of nuclear factor-kappa B (NF-kappaB), and degradation of IkappaB and subsequent activation of NF-kappaB occurred in response to PMA treatment. These findings indicate that PMA induces expression of cPLA(2)alpha at the transcriptional level via an NF-kappaB-dependent mechanism. In addition, activation of the NF-kappaB promoter by PMA was diminished by pretreatment with DPI, a flavoenzyme inhibitor as well as by rottlerin, suggesting a role for reactive oxygen species (ROS) as well as PKCdelta. Consistent with this. PMA stimulated the production of ROS and this was blocked by inhibiting PKCdelta. Our results suggest that PKCdelta and ROS lie upstream of NF-kappaB, and we conclude that a PKCdelta-ROS-NF-kappaB cascade plays a pivotal role in cPLA(2)alpha induction by PMA. (C) 2004 Elsevier Inc. All rights reserved.