Ex vivo lipopolysaccharide-induced interleukin-1 secretion from murine peritoneal macrophages inhibited by probucol, a hypocholesterolemic agent with antioxidant properties.
Probucol, 4,4'-(isopropylidenedithio)bis(2,6-di-tert-butyl-phenol), has been shown to inhibit atherogenesis in genetically hypercholesterolemic (Watanabe) rabbits. Since atherosclerotic lesions contain macrophages capable of screting interleukin 1 (IL 1) and other cytokines that could contribute to the pathogenesis of the disease, we have investigated whether probucol affects IL 1 secretion. Resident peritoneal macrophages from mice dosed with probucol secreted 40-80% less IL 1 than macrophages from control animals when stimulated in vitro with lipopolysaccharide (LPS). The inhibitory effect of probucol was observed when IL 1 was assayed by the standard bioassay, the thymocyte proliferation assay, or a competitive IL 1 receptor binding assay. Probucol treatment had no effect on LPS-induced membrane IL 1 expression; secretion of tumor necrosis factor (TNF); Con A-induced splenic interleukin 2 (IL 2) and interleukin 3 (IL 3) release; and prostaglandin- or zymosan-induced secretion of prostacyclin, leukotriene C4, acid phosphatase, or superoxide anion. In contrast to the effect of oral administration, direct addition of probucol to macrophage cultures did not inhibit IL 1 release. Probucol administration did, however, inhibit the fall in serum zinc level induced by intravenous injection of LPS in zymosan-primed mice but had no effect on the LPS-induced increase in serum triglyceride levels, which indirectly confirms that probucol administration inhibits IL 1 but not TNF secretion. Paw granuloma induced in mice by heat-killed mycobacteria was inhibited by oral administration of probucol, an effect that may be attributable to inhibition of IL 1 secretion. Probucol neither reduced zymosan-induced liver granulomata in mice nor inhibited adjuvant-induced arthritis in rats. We suggest that inhibition of IL 1 secretion from macrophages by probucol contributes to its therapeutic effects in atherosclerosis and may also result in beneficial activity in some chronic inflammatory diseases.
Ku
G
G
Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Doherty
N S
NS
Schmidt
L F
LF
Jackson
R L
RL
Dinerstein
R J
RJ
D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants; D001169:Arthritis, Experimental / Q000503:physiopathology; D002784:Cholesterol / Q000097:blood; D007375:Interleukin-1 / Q000378:metabolism*; D007376:Interleukin-2 / Q000096:biosynthesis; D007377:Interleukin-3 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D010529:Peritoneal Cavity / Q000166:cytology; D010636:Phenols / Q000494:pharmacology*; D011341:Probucol / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D012636:Secretory Rate / Q000187:drug effects; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015032:Zinc / Q000097:blood; D015054:Zymosan
D000975:Antioxidants; D007375:Interleukin-1; D007376:Interleukin-2; D007377:Interleukin-3; D008070:Lipopolysaccharides; D010636:Phenols; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D015054:Zymosan; D002784:Cholesterol; D015032:Zinc; D011341:Probucol