Difference in the ability of compactin and oxidized cholesterol, both known inhibitors of cholesterol biosynthesis, to suppress in vitro immune responses.
Compactin, a fungal metabolite, is a well-characterized competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the enzyme which generally controls the rate of cholesterol biosynthesis in mammalian cells. Various products of cholesterol oxidation, e.g., 25-hydroperoxycholesterol and 25-hydroxycholesterol, also inhibit HMG CoA reductase but by an unknown mechanism which operates only in intact cells. In addition, oxidized cholesterol increases cholesterol esterification and suppresses the increase in low-density lipoprotein receptors which is the normal consequence of decreasing low-density lipoprotein supply. There are therefore, three ways in which the availability of nonesterified cholesterol to mammalian cells is decreased by oxidized cholesterol. It has been suggested that potent in vitro immunosuppression by compounds such as 25-hydroxycholesterol in the presence of cholesterol-containing fetal calf serum is a consequence of their ability to suppress cholesterol biosynthesis. This has been disputed in a previous paper (Humphries, G. M. K., and McConnell, H. M., J. Immunol., 122: 121-126, 1979) because mevalonate, the product of HMG CoA reductase activity, fails to abrogate the suppression. The present paper reports that compactin fails to suppress in vitro immune responses at concentrations known to inhibit HMG CoA reductase (either in the isolated or cellular form). This finding supports the previous conclusion that suppression of HMG CoA reductase activity is not sufficient to inhibit in vitro immune responses in the presence of an exogenous source of cholesterol.[1]References
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