Glycine Inhibits Growth of T Lymphocytes by an IL-2-Independent Mechanism

Abstract

Previously, it was shown that glycine prevented increases in intracellular calcium ([Ca2+]i) in Kupffer cells. Since Kupffer cells and T lymphocytes are derived from the same pluripotent stem cell, it was hypothesized that glycine would prevent increases in [Ca2+]i in lymphocytes and inhibit cell proliferation. Lymphocyte proliferation was measured in one-way MLC with spleen cells from DA and Lewis rats and in enriched T lymphocyte preparations stimulated by immobilized anti-CD3 Ab. Glycine caused a dose-dependent decrease in cell proliferation to about 40% of control. Con A caused a dose-dependent increase in [Ca2+]i in Jurkat cells which was blunted maximally with 0.6 mM glycine. The effect of glycine was dependent on extracellular chloride and reversed by strychnine, an antagonist of the glycine-gated chloride channel. Similar results were obtained with rat T lymphocytes stimulated by anti-CD3 Ab. Surprisingly, glycine had no effect on IL-2 production in the mixed lymphocyte culture; therefore, the effect of glycine on IL-2-dependent proliferation was tested. Glycine and rapamycin caused dose-dependent decreases in IL-2-stimulated growth of Ctll-2 cells to about 60% and 40%, respectively, of control. Moreover, glycine also inhibited the IL-2-stimulated growth of rat splenic lymphocytes. It is concluded that glycine blunts proliferation in an IL-2-independent manner. This is consistent with the hypothesis that glycine activates a glycine-gated chloride channel and hyperpolarizes the cell membrane-blunting increases in [Ca2+]i that are required for transcription of factors necessary for cell proliferation.

Inhibition of primary human T cell proliferation byHelicobacter pylorivacuolating toxin (VacA) is independent of VacA effects on IL-2 secretion

“…Consistent with this view, Boncristiano et al (17) recently reported that VacA could block ionophore-stimulated inf lux of calcium into T cells. Furthermore, a previous study demonstrated that activation of glycine-gated chloride channels induces membrane depolarization of T cells, resulting in a decreased open probability of plasma membrane calcium channels and in the inhibition of IL-2-dependent proliferation without affecting IL-2 secretion or NFAT activation (37).…”

Ryanodine receptor signaling is required for anti‐CD3‐induced T cell proliferation, interleukin‐2 synthesis, and interleukin‐2 receptor signaling

“…Our own data are consistent with a requirement for sustained RyR-mediated intracellular Ca þþ mobilization by T cells in response to IL-2 receptor signaling since (1) anti-CD3-activated T cells that had normal CD25 expression failed to proliferate in response to exogenous IL-2 when RyR were blocked by ruthenium red and (2) IL-2-dependent mouse CTLL-2 cells exhibited a reduced capacity to proliferate in response to IL-2 in the presence of RyR antagonists. In this regard, it is noteworthy that glycine, which blunts anti-CD3-induced increases in intracellular Ca þþ concentration in rat T cells, also inhibits the IL-2-dependent proliferation of mouse CTLL-2 cells [Stachlewitz et al, 2000]. One possibility is that RyRmediated increases in intracellular Ca þþ levels are required for the activation of kinases that regulate T cell proliferation in response to IL-2 receptor signaling.…”

Dietary Glycine Prevents Peptidoglycan Polysaccharide-Induced Reactive Arthritis in the Rat: Role for Glycine-Gated Chloride Channel

“…It can stimulate glycine-gated chloride channels, leading to increased chloride influx that hyperpolarizes neuronal membranes and inhibits excitatory signal transduction (4,26). Recently, glycine has been shown to be immunosuppressive in several studies (35,40). Glycine ameliorates kidney and liver injury during endotoxin shock (12), an effect that was due to the blocking of intracellular calcium signaling and the production of TNF-␣ in hepatic Kupffer cells via a glycine-gated chloride channel (13,41).…”