Studies on a mechanism by which cytosolic phospholipase A(2) regulates theexpression and function of type IIA secretory phospholipase A(2)

Although it has been proposed that arachidonate release by several secretor y phospholipase A(2) (sPLA(2)) isozymes is modulated by cytosolic PLA(2) (c PLA(2)), the cellular component(s) that intermediates between these two sig naling PLA(2)s remains unknown. Here we provide evidence that 12- or 15-lip oxygenase (12/15-LOX), which lies downstream of cPLA(2), plays a pivotal ro le in cytokine-induced gene expression and function of sPLA(2)-IIA. The sPL A(2)-IIA expression and associated PGE(2) generation induced by cytokines i n rat fibroblastic 3Y1 cells were markedly attenuated by antioxidants that possess 12/15-LOX inhibitory activity. 3Y1 cells expressed 12/15-LOX endoge nously, and forcible overexpression of 12/15-LOX in these cells greatly enh anced cytokine-induced expression of sPLA(2)-IIA, with a concomitant increa se in delayed PG generation, Moreover, studies using 293 cells stably trans fected with sPLA(2)-IIA revealed that stimulus-dependent hydrolysis of memb rane phospholipids by sPLA(2)-IIA was enhanced by overexpression of 12/15-L OX. These results indicate that the product(s) generated by the cPLA(2)-12/ 15-LOX pathway following cell activation may play two roles: enhancement of sPLA(2)-IIA gene expression and membrane sensitization that leads to accel erated sPLA(2)-IIA-mediated hydrolysis.