Leukotriene B4 modulates phospholipid methylation and chemotaxis in human polymorphonuclear leukocytes.
Formation of phosphatidylcholine from phosphatidylethanolamine via the S-adenosylmethionine (AdoMet) pathway has been shown to be required for signal transduction of receptor-ligand interactions in a variety of cells. These interactions result in the remodeling of phospholipid pools and phospholipase activation. To extend these observations and to explore the role of the phosphatidylcholine synthesis pathway in transduction of the leukotriene B4 (LTB4) receptor-ligand response, we examined phospholipid methylation in human polymorphonuclear leukocytes (PMN) following stimulation by LTB4, a potent chemotactic agent that is a metabolite of arachidonic acid. At early time points (approximately 3-10 min), formation of methylated phospholipids was enhanced following LTB4 stimulation. The LTB4 analogs 6-trans LTB4 as well as LTB4 epimers induced less methylation compared with LTB4, and the potencies of these analogs in inducing methylation correlated with their diminished ability to induce chemotaxis. Furthermore, the ability of these agonists to induce methylation also correlated with the binding affinity of these agents to the LTB4 receptors on these cells. Synthesis of phosphatidylcholine by the choline transferase pathway was not affected by LTB4. Inhibition of the AdoMet reaction with 3- deazaadenosine, L-homocysteine homolactone, or erythro-9-[2-hydroxy-3-nonyl] adenine (EHNA) abrogated LTB4-induced phospholipid methylation and the chemotactic response. The potencies of these inhibitors in blocking phospholipid methylation also correlated with their ability to abrogate the LTB4-induced chemotactic response. These data suggest that phospholipid methylation and phospholipase activation play an important role in transduction of the LTB4 receptor-ligand interaction in PMN, which results in chemotaxis.
Bomalaski
J S
JS
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia.
Dundee
D
D
Brophy
L
L
Clark
M A
MA
D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000494:pharmacology*; D008715:Methionine / Q000378:metabolism; D008745:Methylation; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D010713:Phosphatidylcholines / Q000096:biosynthesis; D010743:Phospholipids / Q000378:metabolism*; D013237:Stereoisomerism; D014372:Tubercidin / Q000494:pharmacology
D010713:Phosphatidylcholines; D010743:Phospholipids; C018258:3-deazaadenosine; D007975:Leukotriene B4; D008715:Methionine; D014372:Tubercidin