Up-regulation of cyclooxygenase-2 (COX-2) and down-regulation of 15-prostaglandin dehydrogenase (15-PGDH) has been hypothesized to lead to a pro-proliferative, angiogenic, and chronically inflamed state.  Aside from their relatively well-studied prostaglandin production, COXs also mediate the metabolism of arachidonic acid (AA) to hydroxyeicosatetraenoic acids (HETEs), which can then be further oxidized by dehydrogenases to the corresponding keto-products. We have previously established that 11-oxo-eicosatetraenoic acid (oxo-ETE) is a major COX-2/15-PGDH derived metabolite. 11-oxo-ETE has been identified from human isolates yet currently has no known receptors or known physiologic function, however studies had indicated that molecules possessing a similar a,�-unsaturated ketone moiety may act as canonical Nuclear Factor-?B (NF-?B) inhibitors.  Thus we investigate this hypothesis for 11-oxo-ETE and we demonstrate here that it can enter cells, inhibit p50/p65 NF-?B subunit binding to DNA, inhibit a firefly luciferase NF-?B reporter, and covalently adduct a critical cysteine in the DNA binding region of p65.

Cyclooxygenase-2/15-prostaglandin dehydrogenase derived endogenous canonical NF-κB inhibitors

244th National Meeting (2012)

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