Leukotriene B 4 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 B 4 (LTB 4 ) receptor–ligand response, we examined phospholipid methylation in human polymorphonuclear leukocytes (PMN) following stimulation by LTB 4 , a potent chemotactic agent that is a metabolite of arachidonic acid. At early time points (~3–10 min), formation of methylated phospholipids was enhanced following LTB 4 stimulation. The LTB 4 analogs 6‐trans LTB 4 as well as LTB 4 epimers induced less methylation compared with LTB 4 , 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 LTB 4 receptors on these cells. Synthesis of phosphatidylcholine by the choline transferase pathway was not affected by LTB 4 . Inhibition of the AdoMet reaction with 3‐ deazaadenosine, L‐homocysteine homolactone, or erythro‐9‐[2‐hydroxy‐3‐nonyl] adenine (EHNA) abrogated LTB 4 ‐induced phospholipid methylation and the chemotactic response. The potencies of these inhibitors in blocking phospholipid methylation also correlated with their ability to abrogate the LTB 4 ‐induced chemotactic response. These data suggest that phospholipid methylation and phospholipase activation play an important role in transduction of the LTB 4 receptor–ligand interaction in PMN, which results in chemotaxis.