Resistance of activated human Th2 cells to NO-induced apoptosis is mediated by γ-glutamyltranspeptidase
Resistance of activated human Th2 cells to NO-induced apoptosis is mediated by γ-glutamyltranspeptidase
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DOI：
10.1093/intimm/13.4.519
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发表时间：
2001-04-01
影响因子：
4.4
通讯作者：
Kauffman, HF
中科院分区：
文献类型：
--
作者：
Roozendaal, R;Vellenga, E;Kauffman, HF
活化诱导的炎性细胞死亡（AICD）在免疫维持中具有重要作用，已知1型T-h细胞比T（h）2细胞更易受AICD的影响。在目前的研究中，我们检查是否NO诱导的凋亡也优先消除T（h）1细胞超过Th 2细胞。用IL-12+抗IL-4或IL-4+抗IL-12分别激活人Th淋巴细胞（CD 4（+）CD 45 RO（-））1周，使其产生T（h）1和T（h）2极化细胞。我们发现，在10 μ M Sper存在下，通过Annexin染色证实，NO优先诱导T（h）1极化细胞的凋亡（70 +/- 16对23 +/- 4.4%，T（h）2细胞P < 0.01）和DioC（6）染色NO诱导T（h）1/T（h）2极化细胞凋亡的机制与AICD和Pas诱导的凋亡不同。T（h）1和T（h）2极化培养物之间的差异敏感性起源于细胞内谷胱甘肽（GSH）代谢水平。T（h）2细胞的GSH水平高于T（h）1细胞（1.6 ± 0.2倍，P <0.01）。在T（h）2极化细胞中高的细胞内GSH不能解释对NO本身敏感性的降低，因为参与GSH输入的γ-谷氨酰转肽酶（gamma -GT）的抑制使T（h）2细胞对NO诱导的凋亡敏感，而没有GSH耗竭。因此，Th 2细胞中较高的γ-GT活性（2.1 ± 0.4倍T（h）1，P < 0.001）特异性地保护T（h）2细胞免受NO诱导的凋亡。
Activation-induced death of inflammatory cells (AICD) has an important function in immune maintenance, Type 1 T-h cells are known to be more susceptible to AICD than T(h)2 cells. In the current study we examined whether NO-induced apoptosis also preferentially eliminates T(h)1 cells over Th2 cells. Naive human Th lymphocytes (CD4(+)CD45RO(-)) were activated in vitro for 1 week in the presence of IL-12 plus anti-IL-4 or IL-4 plus anti-IL-12 to generate T(h)1- and T(h)2-polarized cultures respectively, Cultures were exposed to the NO donors Spermine-nonoate (Sper) and DPTA-nonoate to study NO-induced apoptosis. We found that NO preferentially induced apoptosis in T(h)1-polarized cells as demonstrated by Annexin staining in the presence of 10 muM Sper(70 +/- 16 versus 23 +/- 4.4% in T(h)2 cells P < 0.01) and by DioC(6) staining (38 10 versus 11 +/- 5% in T(h)2 cells, P < 0.01), The mechanism of NO-induced apoptosis in T(h)1/T(h)2-polarized cells was distinct from AICD and Pas-induced apoptosis, Differential sensitivity between T(h)1- and T(h)2-polarized cultures originated at the level of intracellular glutathione (GSH) metabolism. GSH levels were higher in T(h)2 cells (1.6 0.2-fold T(h)1, P < 0,01). High intracellular GSH in T(h)2-polarized cells did not account for reduced susceptibility to NO per se, since the inhibition of -glutamyltranspeptidase (gamma -GT), which is involved in GSH import, sensitized T(h)2 cells to NO-induced apoptosis without GSH depletion. Therefore, higher activity of gamma -GT in Th2 cells (2.1 +/- 0.4-fold T(h)1, P < 0.001) specifically protects T(h)2 cells against NO-induced apoptosis, Preferential NO-induced elimination of human T(h)1 cells at sites of inflammation may thus select Th2 cells and contribute to immune deviation.