Modulation of human t cell responses by nitric oxide and its derivative, s‐nitrosoglutathione

Objective. To examine the effects of nitric oxide (NO) and its more stable derivative, S‐nitrosoglutathione (SNO‐GSH), on the response of activated T lymphocytes. Methods. The effects of NO and SNO‐GSH on DNA synthesis, interleukin‐2 (IL‐2) production, IL‐2 receptor expression, and cGMP accumulation were determined in phytohemagglutinin–activated peripheral blood mononuclear cells (PBMC) and spleen T cells. Results. Nitric oxide (half‐life [T1/2] < 15 seconds) did not inhibit T cell proliferation. However, the derivative SNO‐GSH (25 μM) (T1/2 >2 hours) inhibited DNA synthesis by a mean ± SD of 65 ± 19.6% (P < 0.001) in PBMC and 75 ± 15% (P < 0.001) in spleen cells. Macrophage depletion of PBMC did not abrogate the inhibition. SNO‐GSH had no effect on IL‐2 production or IL‐2 receptor expression. NO (25 μM) increased the cGMP content of PBMC (0.65 ± 0.15 pmoles/106 cells; P < 0.04), as did SNO‐GSH (25 μM) in both PBMC (3.8 ± 1; P < 0.001) and spleen T cells (5.2 ± 1.2; P < 0.001). Methylene blue and hemoglobin, which are NO inhibitors, inhibited SNO‐GSH–induced cGMP accumulation (P < 0.001). Conclusion. SNO‐GSH inhibits T cell DNA synthesis independently of IL‐2 production and in association with cGMP accumulation via a NO‐dependent mechanism. We suggest that NO and its S‐nitrosothiol derivatives may act as endogenous inhibitors of T cell–mediated inflammation.