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

Abstract

Abstract 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 [T 1/2 ] &lt; 15 seconds) did not inhibit T cell proliferation. However, the derivative SNO‐GSH (25 μ M ) (T 1/2 &gt;2 hours) inhibited DNA synthesis by a mean ± SD of 65 ± 19.6% ( P &lt; 0.001) in PBMC and 75 ± 15% ( P &lt; 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 μ M ) increased the cGMP content of PBMC (0.65 ± 0.15 pmoles/10 6 cells; P &lt; 0.04), as did SNO‐GSH (25 μ M ) in both PBMC (3.8 ± 1; P &lt; 0.001) and spleen T cells (5.2 ± 1.2; P &lt; 0.001). Methylene blue and hemoglobin, which are NO inhibitors, inhibited SNO‐GSH–induced cGMP accumulation ( P &lt; 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.