Inhibition of phytohemagglutinin-induced lymphocyte mitogenesis by lipoxygenase metabolites of arachidonic acid: structure-activity relationships
1984
Phytohemagglutinin (PHA)-induced mitogenesis of mixed mouse spleen lymphocyte populations, measured by ('Hlthymidine incorporation, was completely inhibited by mi- cromolar concentrations of certain hydroxyeicosatetraenoic acids (HETE's). These are lipoxygenase metabolites of arachi- donic acid which are synthesized in considerable concentrations by macrophages, lymphocytes, and other components of the immune system when appropriately stimulated. In the studies described here, the structural requirements for the maximum antimitogenic activities were examined. A series of monohy- droxylated HETE's were prepared using a singlet oxygen photochemical procedure or by enzymatic synthesis from ara- chidonic acid substrate, and isolated by HPLC. Isomers con- taining different numbers of double bonds were synthesized using the appropriate unsaturated fatty acid as substrate, and the functional importance of the OH and carboxylic functions was tested using various acetoxy- and carbomethoxy derivatives. A serum-free mitogenesis assay system was used for testing, which minimized binding of the fatty acids by serum proteins and increased the inhibitory potency of the various HETE's several-fold. It was found that inhibition of cell proliferation was related to: I) hydroxyl proximity to the center of the eicosatetraenoic acid, decreasing in the order: 9 > 11 > 12 > 15 > 8 p 5; 2) the number of double bonds in the fatty acid chain, decreasing in the order: 15-OH, 20:4 > 15-OH, 203 & 15-OH, 20:2 & 15-OH, 20:O; and 3) the 15-position functional group as well as the l-carboxylic group, decreasing in the order: 1 5-hydroxy, 1-carboxylic > 15-acetoxy, l-carbox- ylic & 15-hydroxy, l-carbomethoxy > 15-acetoxy, l-carbome- thoxy. The data indicate considerable structural specificity, requiring that the inhibitor has more than two double bonds, an unshielded carboxylic acid group at the beginning of the fatty acid chain, and a hydroxy1 group in close proximity to the center of the molecule. The results obtained here may be relevant to the physiological function of the mono-hydroxyei- cosanoic acids under in vivo conditions.--low, CE., M. B. Pupillo, R. W. Bryant, and J. M. Bailey. Inhibition of phytohemagglutinin-induced lymphocyte mitogenesis by lipox- ygenase metabolites of arachidonic acid: structure-activity re-
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