The DNA synthetic response of normal and abnormal human lymphocytes to mevalonic acid: the role of granulocytes as a helper population.

In order to investigate the role of neutrophils in the DNA synthetic response of human peripheral blood lymphocytes to mevalonic acid, we obtained preparations of both cells each free of cross-contamination by the other. Purified lymphocytes respond poorly to mevalonic acid, but their response can be significantly enhanced by one half their number of neutrophils. Preincubation of lymphocytes with neutrophils for 24 hr, even in the absence of mevalonic acid, further increases the lymphocyte response. We have been unable to demonstrate the production by granulocytes of either an intracellular or extracellular mevalonate-derived growth factor that in turn stimulates lymphocytes. Granulocytes preexposed to mevalonate do not acquire the ability to stimulate lymphocyte DNA synthesis in the absence of mevalonate. Our experiments suggest that neither neutrophil lysosomal enzymes nor reactive oxygen species generated by neutrophils are responsible for the help neutrophils provide. Normal E rosette-positive lymphocytes fail to respond to mevalonate, whereas E rosette-negative cells do. The mevalonate response of normal E rosette-negative cells is enhanced by the presence of granulocytes in contrast to B cell-chronic lymphocytic leukemia cells that synthesize DNA briskly in response to mevalonic acid in the absence of neutrophil help. These observations add to our knowledge of the relationship between mevalonate metabolism and the regulation of cellular DNA synthesis and mitosis.