Inhibition of T-lymphocyte proliferation by the cyclic polypeptide didemnin B: no inhibition of lymphokine stimulation.

Abstract

We investigated possible mechanisms by which the cyclic depsipeptide didemnin B (DB) inhibits lymphocyte proliferation. DB inhibited the proliferation of Con-A stimulated murine splenocytes, the interleukin-2 (IL-2) dependent proliferation of the CTLL-2 cell line, and the interleukin 4 (IL 4) dependent growth of both CTLL-2 and D10.G.4.1 cell lines at approximately equimolar concentrations (SD50 = 3 to 10 X 10(-9)M). Inhibition of CTLL-2 growth by 10(-8)M DB was partially reversible, and significantly blocked the incorporation of [3H]-thymidine even when added 24 hr after initial IL 2 stimulation. Concentrations of DB (10(-8)M) that completely blocked mitogen-driven spleen cell blastogenesis only partially inhibited the synthesis and secretion of IL-2. Although DB blocked the growth of T lymphocyte clones in response to both recombinant human IL 2 and recombinant murine IL 4, the suppression was not due to an uncoupling of lymphokinetic signaling but was closely correlated with an inhibition of protein and RNA synthesis. Addition of DB to an in vitro translation system did not inhibit protein synthesis. Thus, we conclude that DB functions as an antiproliferative, and not as a specifically immunosuppressive, compound.