Glutathione modulates activation-dependent proliferation of human peripheral blood lymphocyte populations without regulating their activated function.
L-Buthionine-(S,R)-sulfoximine (BSO) specifically depletes GSH synthesis by inactivating gamma-glutamylcysteine synthetase, whereas 2-ME augments intracellular GSH concentration. These reagents were used to examine GSH regulation of the proliferation and function of human PBL in response to IL-2 or OKT-3 mAb directed at the CD3 T cell Ag. 2-ME enhanced both IL-2-induced proliferation of PBL and CD3- large granular lymphocytes (LGL) and OKT-3 mAb-induced proliferation of CD3+ T cells. BSO partially suppressed activation-induced proliferation in CD3- LGL and CD3+ T cells and totally inhibited the positive co-proliferative regulation by 2-ME in these cells. By contrast, neither BSO nor 2-ME appeared to affect the activation-dependent differentiation of cytotoxic lymphocytes. The absence of effect of 2-ME or BSO on activation-induced PBL NK activity and T cell cytotoxic potential was supported by their negligible effect on the induction of two different markers of activated cytotoxic lymphocytes, namely pore-forming protein gene expression and benzoyloxycarbonyl-1-L-lysine thiobenzylester-esterase activity. BSO inhibition of CD3- LGL proliferation accounted for the inhibitory effects of BSO on both IFN-gamma production in IL-2-stimulated PBL cultures and IL-2-induced PBL lymphokine activated killer activity. The modulatory effects of 2-ME and BSO on lymphocyte proliferation regardless of phenotype (LGL vs T cell) or stimulation (IL-2, via CD3, lectin, etc.) and the functional differentiation of cytotoxic lymphocytes independent of proliferation suggests that these cells share a common site of GSH regulation close to or at the level of DNA synthesis.
Smyth
M J
MJ
Laboratory of Experimental Immunology, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702-1201.
D000963:Antimetabolites / Q000494:pharmacology; D019328:Buthionine Sulfoximine; D002455:Cell Division / Q000187:drug effects; D005978:Glutathione / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000502:physiology; D015979:Killer Cells, Lymphokine-Activated / Q000502:physiology; D007694:Killer Cells, Natural / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology*; D008623:Mercaptoethanol / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D013601:T-Lymphocytes / Q000502:physiology
D000963:Antimetabolites; D007376:Interleukin-2; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D008623:Mercaptoethanol; D005978:Glutathione