Arachidonic acid influences proinflammatory gene induction by stabilizing the inhibitor-kappaBalpha/nuclear factor-kappaB (NF-kappaB) complex, thus suppressing the nuclear translocation of NF-kappaB.
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-kappaB (NF-kappaB) to the nucleus by blocking the degradation of the inhibitor of NF-kappaB (IkappaB) and thus stabilizing the IkappaB/NF-kappaB complex. To investigate the mechanism whereby AA inhibits up-regulation of genes encoding proinflammatory mediators, we examined the ability of ETYA to inhibit tumor necrosis factor-alpha (TNF-alpha) mediated phosphorylation and degradation of IkappaBalpha. Western blot analysis revealed that preincubation of EC with ETYA for 40 min prior to stimulation with TNF-alpha inhibits the phosphorylation and degradation of IkappaBalpha. These findings establish a mechanism by which AA inhibits nuclear translocation of NF-kappaB and thereby explaining its modulatory role in the induction of proinflammatory genes.
Stuhlmeier
K M
KM
Sandoz Center for Immunobiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. kstuhlm@nedhmail.nedh.harvard.edu
Kao
J J
JJ
Bach
F H
FH
D000818:Animals; D016718:Arachidonic Acid / Q000235:genetics / Q000494:pharmacology*; D001692:Biological Transport; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006868:Hydrolysis; D018836:Inflammation Mediators / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D013552:Swine; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation
D018836:Inflammation Mediators; D016328:NF-kappa B; D016718:Arachidonic Acid