INHIBITION OF PROLIFERATION AND OF IL-2 PRODUCTION AND UTILIZATION INLYMPHOCYTES BY S-OXALYLGLUTATHIONE

Previously we have shown that S-oxalins (monothiolesters of oxalic aci d) are ubiquitous mammalian metabolites whose concentrations decrease when lymphocytes are stimulated to proliferate. The present study was undertaken to further examine the role of S-oxalins in the proliferati on process. When added to lymphocytes stimulated with concanavalin A, the S-oxalin, S-oxalylglutathione (GS-Ox), inhibited DNA synthesis by 50% when present at ca. 0.15 mM and virtually 100% at 0.5 mM. The inhi bition was reversible. The presence of GS-Ox blocked IL-2 production, but addition of IL-2 did not permit DNA synthesis to proceed. GS-Ox al so inhibited proliferation of an IL-2-dependent cell line, BT2. Ln pri mary lymphocytes GS-Ox reduced IL-2 receptor expression, but not in an IL-2-dependent blast cell line. Overall RNA synthesis and protein syn thesis were not significantly altered by GS-Ox. Levels of the positive transcription factor, NF-kappa B, were decreased after incubation of lymphocytes with GS-Ox, but the amount of a negative transcription fac tor, NREA, was largely unchanged. The results not only provide further evidence that S-oxalins are small-molecule cell proliferation inhibit ors, they also clarify to some extent the specific steps in the activa tion response modulated by S-oxalins. (C) 1996 Academic Press, Inc.