Activation of Guinea Pig Peritoneal Macrophages by Platelet Activating Factor (PAF) and Its Agonists1

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Abstract
The platelet activating factor (PAF: 1-O-alkyl-2-O-acetyl-sn-glycero-3-phospho-choline) and its analogs were examined to determine their effects on guinea pig peritoneal macrophages. 1. PAF activated macrophages, but its effect on macrophages was much weaker than that observed on platelets: the concentration required for 50% maximum activation was 8.5 x 10−6 M for macrophages and 2.9 x 10−10 M for platelets. 2. Three PAF agonists, 1-O-octadecyl-2-O-(N, N-dimethylcarbamoyl)-glycero-3-phosphocholine (Compound 1), 1-O-octadecyl-2-acetamido-2-deoxy-glycero-3-phosphocholine (Compound II), and 1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine (Compound III), showed higher activity in stimulating macrophage function than PAF. The abilities of these non-metabolizable PAF agonists to activate macrophage paralleled their relative potency to induce platelet activation. 3. The sn-3 enantiomers of PAF and Compound III exhibited activity, while the sn-1 did not. By comparing the activities of derivatives of Compound III, it was shown that the long-chain alkyl-ether group in the glycerol-1 position, a relatively small size of the substituent on the hydroxy group at the sn-2 position, and the choline moiety in the glycerol-3 position must play critical roles in the process of macrophage activation. 4. A specific PAF antagonist, CV3988, which inhibits PAF-induced platelet activation and hypotension, inhibited the activation of macrophages caused by PAF and its agonists. 5. Radioactive PAF and Compound III were synthesized and incubated with macrophages. More than 99% of PAF was converted to lysoPAF and 1-alkyl-2-acyl-glycerophosphocholine during a 72 h incubation. On the other hand, 60% of Compound III remained intact. The rapid degradation of PAF may explain why the effect of PAF on macrophages was relatively weak. These results indicate that PAF and PAF agonists cause macrophage activation through specific binding to a macrophage cell surface receptor, which recognizes the structure and configuration of PAF. Our findings support the concept that PAF is a potent mediator in some pathological process.

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