ALTERED RESPONSES OF HUMAN MACROPHAGES TO LIPOPOLYSACCHARIDE BY HYDROPEROXY EICOSATETRAENOIC ACID, HYDROXY EICOSATETRAENOIC ACID, AND ARACHIDONIC-ACID - INHIBITION OF TUMOR-NECROSIS-FACTOR PRODUCTION

The regulation of allergic and autoimmune inflammatory reactions by po lyunsaturated fatty acids and their metabolic products (eicosanoids) c ontinues to be of major interest. Our data demonstrate that arachidoni c acid 5,8,11,14-eicosatetraenoic acid (20:4n-6) and its hydroxylated derivatives 15(s)-hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE) an d 15(s)-hydroperoxy-5,8,11,13-eicosatetraenoic acid (15-HPETE) regulat e agonist-induced tumor necrosis factor alpha (TNF) production, a cyto kine that plays a role in inflammatory diseases. Although 20:4n-6 and 15-HETE caused a reduction in production of TNF in mononuclear leukocy tes stimulated with phytohaemagglutinin, pokeweed mitogen, concanavali n A, and Staphylococcus aureus, 15-HPETE was far more active. 15-HPETE was also found to dramatically depress the ability of bacterial lipop olysaccharide to induce TNF production in monocytes and the monocytic cell line Mono Mac 6. These fatty acids depressed the expression of TN F mRNA in Mono Mac 6 cells stimulated with LPS; 15-HPETE was fivefold more active than 20:4n-6 and 15-HETE. While 15-HPETE treatment neither affected LPS binding to Mono Mac 6 cells nor caused a decrease in CD1 4 expression, the fatty acid significantly reduced the LPS-induced tra nslocation of PKC (translocation of alpha, beta I, beta II, and epsilo n isozymes), suggesting that 15-HPETE acts by abrogating the early sig nal transduction events. The findings identify another molecule that c ould form the basis for development of antiinflammatory pharmaceutical s.