8-11-14-eicosatrienoic-acid and Crohn-Disease

The epoxygenase CYP2J2 has an emerging role in inflammation and vascular biology. The role of CYP2J2 in phagocytosis is not known and its regulation in human inflammatory diseases is poorly understood. Here we investigated the role of CYP2J2 in bacterial phagocytosis and its expression in monocytes from healthy controls and Crohns disease patients. CYP2J2 is anti-inflammatory in human peripheral blood monocytes. Bacterial LPS induced CYP2J2 mRNA and protein. The CYP2J2 arachidonic acid products 11,12-EET and 14,15-EET inhibited LPS induced TNFα release. THP-1 monocytes were transformed into macrophages by 48h incubation with phorbol 12-myristate 13-acetate. Epoxygenase inhibition using a non-selective inhibitor SKF525A or a selective CYP2J2 inhibitor Compound 4, inhibited E. coli particle phagocytosis, which could be specifically reversed by 11,12-EET. Moreover, epoxygenase inhibition reduced the expression of phagocytosis receptors CD11b and CD68. CD11b also mediates L. monocytogenes phagocytosis. Similar, to E. coli bioparticle phagocytosis, epoxygenase inhibition also reduced intracellular levels of L. monocytogenes, which could be reversed by co-incubation with 11,12-EET. Disrupted bacterial clearance is a hallmark of Crohn's disease. Unlike macrophages from control donors, macrophages from Crohn's disease patients showed no induction of CYP2J2 in response to E. coli. These results demonstrate that CYP2J2 mediates bacterial phagocytosis in macrophages, and implicates a defect in the CYP2J2 pathway may regulate bacterial clearance in Crohn's disease.

Topics: 8,11,14-Eicosatrienoic Acid; Antigens, CD; Antigens, Differentiation, Myelomonocytic; CD11b Antigen; Cell Line; Crohn Disease; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Enzyme Induction; Escherichia coli; Female; Humans; Lipopolysaccharides; Macrophages; Male; Monocytes; Phagocytosis

To determine fatty acid patterns in Crohn's disease, we measured various serum fatty acids by gas chromatography in 20 patients with the disease and compared them with those in 18 healthy controls. All the patients had been free from any nutritional supplementation during preceding six months or had no history of intestinal resection. Eight of the patients were affected in the small bowel only, three in the large bowel only, and the remaining nine in both the small and large bowel. Both serum concentrations and percentages of C20:4n6, C20:5n3, C22:0, C22:6n3, total n3 polyunsaturated fatty acids, and total polyunsaturated fatty acids were lower in the patients than in the controls. Both essential fatty acids (C18:2n6, C18:3n3) and C20:3n9 levels were not different between the two groups. Among nine fatty acids that correlated with the Crohn's disease activity index, C20:5n3 and total n3 polyunsaturated fatty acids showed the most significant negative correlations. These findings suggest that essential fatty acid deficiency rarely occurs in Crohn's disease and also that n3 polyunsaturated fatty acids may be relevant to the activity of the disease.

Topics: 8,11,14-Eicosatrienoic Acid; Adult; Chromatography, Gas; Crohn Disease; Fatty Acids, Essential; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Female; Humans; Male; Severity of Illness Index