Influence of polyunsaturated fatty acids on lipid metabolism in human blood mononuclear cells and early biochemical events associated with lymphocyte activation.
n-3 and n-6 polyunsaturated fatty acids are involved in the regulation of the immune response. Although different hypotheses related to modifications of arachidonic acid metabolism or alterations at the level of the cell membrane have been put forward to explain their suppressive effect on the lymphocyte growth, their mechanism of action remains largely unknown. Cyclic nucleotide phosphodiesterase (PDE) has been shown to be an important target involved in the control of lymphocyte proliferation. The present study aimed to determine whether in vitro addition of a physiological concentration (5 microM) of n-6 (20:3n-6) or n-3 (18:4n-3, 20:5n-3, 22:6n-3) fatty acids to human peripheral blood mononuclear cells (PBMC) was able to alter the PDE activity of these cells, and especially the PDE increase in response to Con A stimulation. Pretreatment of human PBMC for a short period of time (90 min) with 5 microM of either 20:3n-6, 20:5n-3 or 22:6n-3 was sufficient to induce a significant enrichment of cellular phospholipids in the corresponding fatty acid, whereas 18:4n-3 was poorly incorporated. Either fatty acid significantly increased both cAMP- and cGMP-PDE activities in the cytosolic compartment, the particulate PDE activities being less sensitive to their stimulatory effect. In contrast, they significantly lowered the PDE increase to Con A stimulation. Except 20:5 n-3, the three other fatty acids did not alter significantly the basal or Con A-induced oxygenated metabolism of arachidonic acid (AA), appreciated by the measurement of radioactive eicosanoids formed in [3H]AA-labelled cells. Furthermore, only 20:5n-3 significantly inhibited the lymphoproliferative response to Con A, whereas 16:0, 18:0, 18:1n-9, 20:3n-6 and 20:4n-6 were inactive. The inhibitory effect was not prevented by antioxidant vitamins C and E. The present results suggest that the lymphocyte growth suppressive effect of 20:5n-3 20:5n-3 is very likely to be independent on both the cAMP system and eicosanoid synthesis, and does not seem to involve their conversion to peroxidised products.
Joulain
C
C
Institut National de la Santé et de la Recherche Médicale U 352, Institut National des Sciences Appliquées de Lyon, Villeurbanne, France.
Guichardant
M
M
Lagarde
M
M
Prigent
A F
AF
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000097:blood; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000097:blood / Q000187:drug effects; D016718:Arachidonic Acid / Q000097:blood; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D008055:Lipids / Q000097:blood*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000502:physiology*; D010743:Phospholipids / Q000097:blood
D005231:Fatty Acids, Unsaturated; D008055:Lipids; D010743:Phospholipids; D003208:Concanavalin A; D016718:Arachidonic Acid; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015106:3',5'-Cyclic-GMP Phosphodiesterases