Mitogenesis in normal human fibroblasts by polyinosinic . polycytidylic acid and other synthetic acidic polymers: enhancement of action by glucocorticoids.

Abstract

The ability of specific synthetic polyelectrolytes to act as mitogens for quiescent normal human fibroblasts in cultures is described. Of several acidic polymers tested, polyinosinic acid .polycytidylic acid (poly I.poly C) and dextran sulfate were the most effective in stimulating 3H]thymidine incorporation (2-to 10-fold). The concentration for a half-maximal effect (ED50) was 0.4 microgram/ml (0.8 nM) for poly I.poly C, and 1.7 microgram/ml (3.4 nM) for dextran sulfate. Single-stranded polyinosinic acid or polycytidylic acid had no effect. The time course of stimulation of DNA synthesis by these acidic polymers was similar to that for naturally occurring mitogens such as epidermal growth factor, beginning at about 18 hours and reaching a maximum rate 26 to 30 hours after the addition of polymer. Glucocorticoids that have an 11-beta hydroxyl group (e.g., dexamethasone) had no effect on DNA synthesis alone, but enhanced several-fold the mitogenic activity of poly I.poly C or dextran sulfate; the ED50 for dexamethasone was 0.75 ng/ml (1.9 nM). Glucocorticoids with an 11-keto group were inactive in this respect. The labeling index following treatment of cultures with poly I.poly C and dexamethasone was 14%, compared with a labeling index of 25% following stimulation by fetal calf serum. The extent of stimulation of DNA synthesis by poly I.poly C and dexamethasone was comparable to that induced by epidermal growth factor. It appears that both the poly I.poly C and dexamethasone are required for only a short period of time (approximately 3 hours) in order to produce maximal stimulation of DNA synthesis 30 hours later.