Arachidonic acid influences proinflammatory gene induction by stabilizing the inhibitor-κBα/nuclear factor-κB (NF-κB) complex, thus suppressing the nuclear translocation of NF-κB

Abstract

Arachidonic acid (AA), through its myriad metabolites, is involved in inflammation in a number of ways. AA is produced and released by several cell types, including endothelial cells (EC), and acts on a variety of cells. EC activation plays a key role in inflammation presumably by modulating the immune response through up- or down-regulation of several genes. We have previously shown that AA and its nonmetabolizable analogue, 5,8,11,14- eicosatetraynoic acid (ETYA), inhibit up-regulation of proinflammatory genes in EC. In the present study we identify a mechanism to explain the inhibitory effects: AA and ETYA both inhibit the translocation of nuclear factor-κB (NF-κB) to the nucleus by blocking the degradation of the inhibitor of NF- κB (IκB) and thus stabilizing the IκB/NF-κB complex. To investigate the mechanism whereby AA inhibits upregulation of genes encoding proinflammatory mediators, we examined the ability of ETYA to inhibit tumor necrosis factor- α (TNF-α) mediated phosphorylation and degradation of IκBα. Western blot analysis revealed that preincubation of EC with ETYA for 40 min prior to stimulation with TNF-α inhibits the phosphorylation and degradation of IκBα. These findings establish a mechanism by which AA inhibits nuclear translocation of NF-κB and thereby explaining its modulatory role in the induction of proinflammatory genes.