Model of the mechanism of oxidized EPA-mediated down-regulation of LPS-induced endothelial-leukocyte interactions.

LPS interacts with the toll-like receptor (TLR) on endothelial cells, which ultimately leads to the phosphorylation of the NFκB inhibitor IκB, which is subsequently rapidly polyubiquinated and degraded by the proteosome. Released NFκB subunits (p65/p50) translocate from the cytoplasm to the nucleus where they bind to NFκB response elements on target genes such as E-selectin and VCAM-1 and drive their transcription. Oxidized EPA is taken up by endothelial cells and activates PPARα. PPARα inhibits NFκB activation through partially understood mechanisms and thus abrogates target gene expression. Subsequent down-regulation of LPS-inducible leukocyte adhesion molecule expression at the cell surface leads to a reduction in leukocyte-endothelial interactions.