Cytochrome P450 (CYP)2J2 is an epoxygenase that has anti-inflammatory effects in the cardiovascular system (Node et al., 1999). We have recently shown that CYP2J2 activates peroxisome proliferator-activated receptor (PPAR)-α, a nuclear receptor that also has anti-inflammatory properties (Bishop-Bailey, 2000; Wray et al., 2003). As one anti-inflammatory action of PPARα is to reduce COX-2 expression (Staels et al., 1998), we investigated whether COX-2 expression in monocytes is regulated by endogenous epoxygenases. Murine monocytes cells (J774.2) were maintained in DMEM supplemented with antibiotics/antimycotics and 10% FCS (37°C, 5% CO2, 95% air). Expression of murine CYP2J isoforms were measured by RT-PCR. Cells were incubated (24h) with vehicle, IL-1β (10ng/ml) and PMA (1nM), the epoxygenase inhibitor SKF525A (30μM), or the selective synthetic PPARα agonist GW7647 (10nM), either alone or in combination. Cells were then lysed, and protein samples (10μg) subjected to Western blot analysis for COX-2, β-actin or PPARα (Bishop-Bailey et al., 2002). J774.2 macrophages contain PPARα and mRNA for CYP2J5, CYP2J6 and CYP2J13. IL-1β and PMA induced COX-2 expression; an affect which was completely inhibited by co-incubation with GW7647. The addition of SKF525A alone also strongly induced COX-2. Addition of IL-1β and PMA did not significantly affect SKF525A induced COX-2. The PPARα ligand GW7647 also significantly decreased SKF525A-induced COX-2 expression (Figure 1). These results suggest that monocytes contain active epoxygenases that tonically suppress inflammation by activating PPARα. Epoxygenases, by producing PPARα ligands may therefore represent an important novel anti-inflammatory pathway.