DOCOSAHEXAENOIC ACID SELECTIVELY ATTENUATES INDUCTION OF VASCULAR CELL-ADHESION MOLECULE-1 AND SUBSEQUENT MONOCYTIC CELL-ADHESION TO HUMAN ENDOTHELIAL-CELLS STIMULATED BY TUMOR-NECROSIS-FACTOR-ALPHA

Incorporation of the n-3 polyunsaturated fatty acid docosahexaenoic ac id (DHA) but not eicosapentaenoic acid or n-6 arachidonic acid into hu man umbilical vein endothelial cell (HUVEC) phospholipids dose-depende ntly reduced tumor necrosis factor-alpha (TNF-alpha)-induced surface e xpression of vascular cell adhesion molecule-1 (VCAM-1). In parallel, DHA inhibited TNF-alpha-stimulated monocytic U937 cell adhesion to HUV ECs but did not affect TNF-alpha- or interferon gamma-induced expressi on of intercellular adhesion molecule-1 and endothelial leukocyte adhe sion molecule-1 or VCAM-1 induction by interleukin-1 beta. DHA appeare d to attenuate VCAM-1 transcription, as it reduced induction of VCAM-1 mRNA by TNF-alpha. VCAM-1 induction is regulated by activation of nuc lear factor-B-k, which can be mediated by a TNF-alpha-responsive phosp hatidylcholine-specific phospholipase C (PC-PLC). Gel-shift analysis s howed inhibition of TNF-alpha-induced nuclear factor-B-k mobilization by DHA. While the PC-PLC inhibitor D609 dose-dependently prevented VCA M-1 induction by TNF-alpha, 12-diacyl-glycerol (DAG) stimulated VCAM-1 expression, suggesting that VCAM-1 induction by TNF-alpha may be medi ated by activation of PC-PLC. Treatment with DHA resulted in a fourfol d enrichment in PC. In addition, DHA or D609 but not eicosapentaenoic acid or arachidonic acid suppressed activation of PC-PLC by TNF-alpha, estimated as [C-14]DAG synthesis in prelabeled HUVECs. Incorporation of DHA into phospholipids selectively attenuates VCAM-1 induction by T NF-alpha and subsequent monocytic cell adhesion by inhibition of TNF-a lpha-stimulated PC-PLC activation in HUVECs.