Selective activation of human monocytes by the platelet-activating factor analog 1-O-hexadecyl-2-O-methyl-sn-glycero-3-phosphorylcholine.
The capacity of platelet-activating factor (PAF) and its 2-O-methyl analog (methoxy-PAF) to activate human monocytes, neutrophils and platelets were compared. Both PAF and methoxy-PAF increased monocyte cytotoxicity toward WEHI 164 cells with a maximal increase in cell killing at 100 pM to 1 nM. Methoxy-PAF was slightly, but significantly, more potent than PAF for increasing cytotoxicity. PAF and methoxy-PAF increased monocyte release of TNF two- to three-fold above control release with no difference in their potency. Methoxy-PAF increased cell-associated TNF maximally after 2 to 3 h of incubation and increased TNF release maximally after 5 to 18 h of incubation. PAF induced release of the neutrophil granule enzyme beta-glucuronidase with maximal net release of 15 to 20% at 100 nM PAF whereas methoxy-PAF did not induce release of beta-glucuronidase. Similarly, 10 nM PAF induced 30% platelet aggregation whereas methoxy-PAF induced aggregation only at 1000-fold higher concentrations. Analysis of PAF and methoxy-PAF metabolism by monocyte and serum acylhydrolases indicates that methoxy-PAF is substantially more resistant than PAF to degradation by these enzymes. These observations indicate that methoxy-PAF activates monocytes selectively and suggest that this phospholipid or a related compound could be used for in vivo immunotherapy.
Rose
J K
JK
Department of Medicine, VA Medical Center, San Francisco, CA 94121.
Debs
R A
RA
Philip
R
R
Ruis
N M
NM
Valone
F H
FH
D002470:Cell Survival / Q000187:drug effects; D003602:Cytotoxicity, Immunologic; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D009000:Monocytes / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D010742:Phospholipid Ethers / Q000378:metabolism / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000378:metabolism / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; C026659:edelfosine; D005966:Glucuronidase