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Human peripheral blood lymphocytes, in the presence of human neutrophils, initiate DNA synthesis and cell cycling when exposed to mevalonic acid. The ability of lymphocytes to respond in this manner is a radiosensitive property of cells, whereas the help provided by neutrophils is maintained despite their exposure to x-irradiation. Other organic acid anions, including precursors of mevalonic acid biosynthesis and a variety of products of mevalonate metabolism, fail to initiate DNA synthesis when added to human lymphocytes. Because only the metabolically active R(--) enantiomer of mevalonic acid initiates lymphocyte DNA synthesis, we presume that physiological pathways of mevalonate metabolism are involved. The response to mevalonic acid of ML-236B (compactin)-inhibited lymphocytes is increased, and the threshold concentration of meyalonate at which lymphocyte DNA synthesis first appears is decreased, when the cells are cultured in lipoprotein-containing (as opposed to lipoprotein-depleted) medium. The response to mevalonic acid of lymphocytes cultured in lipoprotein-depleted medium can be enhanced by addition to the cultures of low density lipoprotein but not by addition of high density lipoprotein. Based upon the flux diversion hypothesis of mevalonate metabolism, these observations suggest that a nonsterol product of mevalonate metabolism may be responsible for the initiation of lymphocyte DNA synthesis by mevalonic acid.

proceedings of the national academy of sciences of the united states of america

Neutrophils are required for the DNA synthetic response of human lymphocytes to mevalonic acid: evidence suggesting that a nonsterol product of mevalonate is involved.