Ferlito Marcella, Irani Kaikobad, Faraday Nauder, Lowenstein Charles J
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11689-94. doi: 10.1073/pnas.0600275103. Epub 2006 Jul 20.
NO inhibits cytotoxic T lymphocyte killing of target cells, although the precise mechanism is unknown. We hypothesized that NO decreases exocytosis of cytotoxic granules from activated lymphocytes. We now show that NO inhibits lymphokine-activated killer cell killing of K562 target cells. Exogenous and endogenous NO decreases the release of granzyme B, granzyme A, and perforin: all contents of cytotoxic granules. NO inhibits the signal transduction cascade initiated by cross-linking of the T cell receptor that leads to granule exocytosis. In particular, we found that NO decreases the expression of Ras, a critical signaling component within the exocytic pathway. Ectopic expression of Ras prevents NO inhibition of exocytosis. Our data suggest that Ras mediates NO inhibition of lymphocyte cytotoxicity and emphasize that alterations in the cellular redox state may regulate the exocytic signaling pathway.
一氧化氮（NO）可抑制细胞毒性T淋巴细胞对靶细胞的杀伤作用，尽管其确切机制尚不清楚。我们推测，NO可减少活化淋巴细胞中细胞毒性颗粒的胞吐作用。我们现在证明，NO可抑制淋巴因子激活的杀伤细胞对K562靶细胞的杀伤作用。外源性和内源性NO均可减少颗粒酶B、颗粒酶A和穿孔素的释放：这些都是细胞毒性颗粒的所有成分。NO可抑制由T细胞受体交联引发的信号转导级联反应，该反应会导致颗粒胞吐作用。特别是，我们发现NO可降低Ras的表达，Ras是胞吐途径中的关键信号成分。Ras的异位表达可阻止NO对胞吐作用的抑制。我们的数据表明，Ras介导NO对淋巴细胞细胞毒性的抑制作用，并强调细胞氧化还原状态的改变可能调节胞吐信号通路。
