We have proposed previously that the expression of group IIA secretory phospholipase A 2 (sPLA 2 -IIA), an enzyme implicated in inflammation, is under the control of group IVA cytosolic phospholipase A 2 (cPLA 2 ) and 12/15-lipoxygense (12/15-LOX) in cytokine-stimulated rat fibroblastic 3Y1 cells. Here, we show that the reduction of cytokine-stimulated sPLA 2 -IIA induction by the cPLA 2 inhibitor arachidonyl trifluoromethyl ketone (AACOCF 3 ) is partially overcome by the addition of various lysophospholipids, such as lysophosphatidylcholine (LysoPC). Furthermore, this lysophospholipid effect was enhanced by further addition of 12/15-LOX products, such as 12(S)- or 15(S)-hydroxyeicosatetraenoic acid (HETE) and 13(S)-hydroxyoctadecadienoic acid (HODE), thus substantiating the hypothesis that the expression of sPLA 2 -IIA is selectively regulated by lipid products of the cPLA 2 –12/15-LOX pathway. In an attempt to identify a set of 12/15-LOX-regulated genes, the cDNA subtraction technique, followed by Northern blotting, was performed to screen particular clones, the expression of which was suppressed by the LOX inhibitor nordihydroguaiaretic acid (NDGA). NDGA-sensitive clones identified thus far included sPLA 2 -IIA, cytoplasmic signaling intermediates, several oxygenases, extracellular matrices, secretory proteins, and other cellular proteins. Of these genes, however, only the expression of sPLA 2 -IIA and 14-3-3η was enhanced by 12/15-LOX expression. Taken together, our data suggest that sPLA 2 -IIA represents a particular group of genes, the transcription of which is up-regulated by 12/15-LOX metabolites.