Cyclosporine, FK506, and rapamycin. Some effects on early activation events in serum-free, mitogen-stimulated mouse spleen cells

Abstract

Both cyclosporine and FK506 (FK) inhibit Con A-stimulated mouse spleen cells from entering the cell division cycle at the G0/G1 interface. Rapamycin, a fungal metabolite structurally related to FK, acts later and blocks progress through the cell division cycle at some point in G1. The effect of CsA, FK, and rapamycin drug combinations appeared additive, while certain concentrations of FK and rapamycin appeared to be antagonistic. The early blockade of lymphocyte activation caused by CsA and by FK was not due to altered membrane transport kinetics, nor to perturbation of the dynamic behavior of actin. However, both drugs showed the same specific effects on gene activation over a profile of genes encoding oncoproteins, putative transcription factors, cyclophilin, heat-shock proteins, IL-2, and IL-2-R. Of note was the drug-associated super-induction of krox-24 and reduced induction of krox-20. Both krox-24 and krox-20 encode proteins containing zinc-binding fingers, and are likely to regulate gene transcription, and this is the first report of gene control mechanisms being specifically affected by CsA and by FK.