Inhibition of proliferation and of IL-2 production and utilization in lymphocytes by S-oxalylglutathione.
Previously we have shown that S-oxalins (monothiolesters of oxalic acid) 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 proliferation 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 inhibition 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 also inhibited proliferation of an IL-2-dependent cell line, BT2. In primary lymphocytes GS-Ox reduced IL-2 receptor expression, but not in an IL-2-dependent blast cell line. Overall RNA synthesis and protein synthesis were not significantly altered by GS-Ox. Levels of the positive transcription factor, NF-kappaB, were decreased after incubation of lymphocytes with GS-Ox, but the amount of a negative transcription factor, NREA, was largely unchanged. The results not only provide further evidence that S-oxalins are small-molecule cell proliferation inhibitors, they also clarify to some extent the specific steps in the activation response modulated by S-oxalins.
Grove
D S
DS
Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park 16802, USA. A36@psuvm.psu.edu
Crowl
C V
CV
Gagajewski
A
A
Yang
C S
CS
Reddy
G R
GR
Hamilton
G A
GA
Mastro
A M
AM
D000818:Animals; D001483:Base Sequence; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides; D010070:Oxalates / Q000494:pharmacology; D019815:Oxalic Acid; D014176:Protein Biosynthesis; D011743:Pyrimidines / Q000096:biosynthesis; D012313:RNA / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism
D007376:Interleukin-2; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D010070:Oxalates; D011743:Pyrimidines; D015375:Receptors, Interleukin-2; D014157:Transcription Factors; C052145:S-oxalylglutathione; D012313:RNA; D019815:Oxalic Acid; D005978:Glutathione