The anti-inflammatory effects of polyunsaturated fatty acids (PUFA) have been well documented, however their exact method of action remains elusive. Dendritic cells (DC) are the most potent antigen presenting cell (APC) and we found that n-3 and n-6 PUFA suppressed IL-12p70 and enhanced IL-10 production rendering the DC less inflammatory. Furthermore, PUFA inhibited DC maturation by impeding the upregulation of co-stirnulatory markers and MHCII expression. Given the critical role of IL-12 and IL-10 in T helper cell differentiation we looked at the effects of PUFA-modified DC on subsequent T cell development and found them capable of inhibiting IFN-y, IL-17, IL-2, and IL-4 production from CD4' T cells. PUFA are reported to be natural ligands for PPARy, therefore we investigated whether they exerted their effects on DC maturation by activation of this nuclear receptor. We found PPARy expression was enhanced in PUFA-treated DC, and confocal microscopy revealed an increased association of PPARy with NFkB . However, the PUFA-induced changes in DC cytokine production and cell surface marker expression were not reversed in the presence of the specific PPARy antagonist (GW9662) and were therefore deemed PPARy independent. Finally we carried out a number of feeding studies in mice where a CLAincorporated diet was used to ascertain whether results we recorded in vitro were mirrored in an in vivo situation. Mice fed a CLA-rich diet had less circulating inflammatory cytokines (LL-12p70 and EN-y) following endotoxin challenge in an LPS-shock model. Furthermore, feeding animals a CLA-supplemented diet significantly protected against the development of colitis in a DSS-induced model of inflammatory bowel disease, thus indicating that PUFA can exert beneficial and protective effects in inflammatory disease.