A novel β-oxa polyunsaturated fatty acid downregulates the activation of the IκB kinase/nuclear factor κB pathway, inhibits expression of endothelial cell adhesion molecules, and depresses inflammation

Several novel polyunsaturated fatty acids (PUFAs) that contain either an oxygen or sulfur atom in the β-position were found to exhibit more selective antiinflammatory properties than their natural PUFA counterparts. One of these, β-oxa-23:4n-6, unlike natural PUFAs, lacked ability to stimulate oxygen radical production in neutrophils but caused marked inhibition of agonist-induced upregulation of leukocyte adhesion to cultured human umbilical vein endothelial cells (HUVEC) and E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 expression. In addition, β-oxa-23:4n-6 inhibited acute and chronic inflammatory responses in mice as well as the upregulation of adhesion molecule expression in arterial endothelium. This action of β-oxa-23:4n-6 required a functional 12- but not 5-lipoxygenase or cyclooxygenases, consistent with its metabolism via the 12-lipoxygenase pathway. Whereas β-oxa-23:4n-6 did not affect the activation of mitogen-activated protein kinases by tumor necrosis factor, activation of the IκB kinase/nuclear factor κB pathway was selectively inhibited. These novel PUFAs could form the basis for a potential new class of pharmaceuticals for treating inflammatory diseases, including atherosclerosis.