Inhibition by probucol of interleukin 1 secretion and its implication in atherosclerosis.
Intravenous injection of 1.5 mg of acetylated low-density lipoprotein (LDL) or 100 micrograms of lipopolysaccharide (LPS) to zymosan-primed mice induced a decrease in serum zinc levels measured 6 hours after injection, suggesting the release of interleukin 1 (IL-1). Oral administration of probucol, 100 mg/kg once daily for 14 days, inhibited the LPS-induced fall in serum zinc levels, suggesting inhibition of IL-1 release. Direct evidence for inhibition of IL-1 release by probucol was obtained with an ex vivo system in which, compared with controls, peritoneal macrophages from probucol-treated mice (100 mg/kg orally X 3, or 0.25% in the diet for 3 weeks) secreted 80 to 90% less IL-1 upon LPS stimulation, measured by the C3H/HeJ thymocyte proliferation assay. Inhibition of IL-1 secretion by probucol may contribute to the therapeutic effect of probucol in atherosclerosis since as little as 1 unit of recombinant IL-1 beta was found to induce proliferation of aortic smooth muscle cells. With regard to the endogenous stimulus for IL-1 secretion, oxidized LDL is a putative candidate because it is capable of stimulating peritoneal macrophages to secrete IL-1. Because oxidized LDL is involved in the transformation of macrophages to foam cells, our data on IL-1 induction by oxidized LDL and the mitogenic effect of IL-1 on aortic smooth muscle cells suggest that activated macrophages play an important role in atherogenesis.
Ku
G
G
Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Doherty
N S
NS
Wolos
J A
JA
Jackson
R L
RL
D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000209:etiology; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010636:Phenols / Q000494:pharmacology*; D011341:Probucol / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D015032:Zinc / Q000097:blood; D015054:Zymosan / Q000494:pharmacology
D007375:Interleukin-1; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D010636:Phenols; C032629:acetyl-LDL; D015054:Zymosan; D015032:Zinc; D011341:Probucol