Esterification of 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid into the phospholipids of human peripheral blood mononuclear cells: inhibition of the proliferative response.
12-hydroxy-eicosatetraenoic acid (12-HETE), the lipoxygenase metabolite of arachidonic acid produced by activated platelets, has been shown to accumulate in peripheral blood mononuclear cells (PBMC) of elderly people. 12-HETE being antimitogenic for lymphocytes, its accumulation in blood cells might be involved in the well-known decline in immune function which accompanies aging. Because HETEs have been shown to be rapidly metabolized and/or incorporated into cellular lipids in a variety of cell types, we have investigated the uptake, metabolism, and intracellular distribution of exogenous 12-HETE by human PBMC. [3H]-12-HETE was dose and time dependently incorporated by PBMC and also metabolized to more polar products. These polar metabolites were mainly released extracellularly and only marginally esterfied in phospholipids. Although [3H]-12-HETE radiolabel was preferentially associated with phosphatidylcholine, especially after prolonged labeling incubations or following successive short labeling pulses, a substantial amount of radiolabel was also found associated with phosphatidylinositol (20-50% of the labeled phospholipids). The stability of 12-HETE in the phospholipid pool was comparable to that reported for most other cell types, with 50% of the initial radiolabel being still present after 18 hr. Upon exposure to mitogenic activation, 12-HETE-labeled PBMC released unmodified 12-HETE from phosphatidylinositol. In addition, 12-HETE dose dependently inhibited the proliferative response of PBMC to Con A stimulation. These results suggest that 12-HETE esterification in phospholipids might lead to the generation of unusual lipid second messengers with impaired capacity to transduce activation signals, thus decreasing lymphocyte function.
Joulain
C
C
Institut National de la Santé et de la Recherche Médicale U 352, Villeurbanne, France.
Meskini
N
N
Anker
G
G
Lagarde
M
M
Prigent
A F
AF
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D002455:Cell Division; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D003470:Culture Media; D004305:Dose-Response Relationship, Drug; D004951:Esterification; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D050356:Lipid Metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism*; D013997:Time Factors
D003470:Culture Media; D006893:Hydroxyeicosatetraenoic Acids; D010743:Phospholipids; D003208:Concanavalin A; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid