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Glycine Inhibits Growth of T Lymphocytes by an IL-2-Independent Mechanism¹

Robert F. Stachlewitz^*,, Xiangli Li^*, Scott Smith^*, Hartwig Bunzendahl, Lee M. Graves and Ronald G. Thurman^2,*,

^* Laboratory of Hepatobiology and Toxicology, Departments of Pharmacology and Surgery, University of North Carolina, Chapel Hill, NC 27599

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.

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