Inhibition of human lymphocyte transformation by oxygenated sterol compounds

Abstract

Oxygenated sterol compounds (OSC), potent inhibitors of sterol synthesis in both resting and mitogen-stimulated human lymphocytes, are capable of suppressing the DNA-synthetic response of human peripheral blood lymphocytes to mitogenic lectins, anti-human thymocyte antiserum, and the mixed lymphocyte culture. The most potent OSC are 20α-hydroxycholesterol and 25-hydroxycholesterol, which inhibit DNA synthesis in mitogenstimulated lymphocytes at 7.4 and 3.9 × 10 −6 M, respectively. Lymphocytes which have been exposed to OSC for 18 hr and washed free of inhibitor are fully capable of DNA synthesis when subsequently challenged with mitogen. Suppression of DNA synthesis by OSC is not apparent during the first 24–40 hr of culture. The inhibition of lymphocyte DNA synthesis by OSC can be partially reversed by the addition of 10 −2 M mevalonate to the culture. Sterol synthesis by mitogen-stimulated lymphocytes is enhanced by culturing them in medium supplemented with lipoprotein (and cholesterol-)-depleted serum. In such medium, the 50% inhibitory doses of 25-hydroxycholesterol for suppression of both mitogen-stimulated lymphocyte DNA and sterol synthesis are approximately equal (−3 × 10 −7 M ). Sterol synthesis is a necessary, but not sufficient, part of the program of lymphocyte proliferative response to mitogens; the evidence presented suggests that lymphocytes can utilize exogenous sterol at least partially for the purpose of cell replication.