IL-2 increases human telomerase reverse transcriptase activity transcriptionally and posttranslationally through phosphatidylinositol 3′-kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells
IL-2 increases human telomerase reverse transcriptase activity transcriptionally and posttranslationally through phosphatidylinositol 3′-kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells
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DOI：
10.4049/jimmunol.174.9.5261
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发表时间：
2005-05-01
影响因子：
4.4
通讯作者：
Yamada, O
中科院分区：
文献类型：
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作者：
Kawauchi, K;Ihjima, K;Yamada, O
人端粒酶活性通过T和B细胞中的Ag受体连接来诱导。然而，目前还不清楚端粒酶活性是否与NK细胞的活化和增殖相关。我们发现，端粒酶活性在人类NK细胞系（NK-92），这需要IL-2的增殖，增加24小时内用IL-2刺激后。端粒酶逆转录酶（hTERT）mRNA和蛋白水平与端粒酶活性相关。ERK 1/2和Akt激酶（Akt）被IL-2刺激激活。PI3K抑制剂LY294002可抑制hTERTmRNA和蛋白表达，并抑制hTERT活性，而抑制MEK 1/2进而抑制ERK 1/2的PD98059则无此作用。此外，根赤霉素，热休克蛋白90（Hsp90）的抑制剂，和雷帕霉素，雷帕霉素的哺乳动物靶蛋白（mTOR）的抑制剂，阻断IL-2诱导的hTERT活性和hTERT的核转位，但不是hTERTmRNA的表达。hTERT与Akt、Hsp90、mTOR和p70 S6激酶（S6K）共免疫沉淀，表明这些分子形成物理复合物。IL-2刺激的NK-92细胞中Akt、Hsp90、mTOR和S6 K的免疫沉淀物含有端粒酶活性。此外，Hsp90和mTOR免疫沉淀的原代样品含有端粒酶活性的结果与NK-92细胞的结果一致。这些结果表明，IL-2刺激诱导hTERT活化，并且IL-2诱导的hTERT活化的机制涉及通过包括NK细胞中的PI3K/Akt、Hsp90、mTOR和S6K的途径的转录或翻译后调节。
Human telomerase activity is induced by Ag receptor ligation in T and B cells. However, it is unknown whether telomerase activity is increased in association with activation and proliferation of NK cells. We found that telomerase activity in a human NK cell line (NK-92), which requires IL-2 for proliferation, was increased within 24 h after stimulation with IL-2. Levels of human telomerase reverse transcriptase (hTERT) mRNA and protein correlated with telomerase activity. ERK1/2 and Akt kinase (Akt) were activated by IL-2 stimulation. LY294002, an inhibitor of PI3K, abolished expression of hTERT mRNA and protein expression and abolished hTERT activity, whereas PD98059, which inhibits MEK1/2 and thus ERK1/2, had no effect. In addition, radicicol, an inhibitor of heat shock protein 90 (Hsp90), and rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), blocked IL-2-induced hTERT activity and nuclear translocation of hTERT but not hTERT mRNA expression. hTERT was coimmuno-precipitated with Akt, Hsp90, mTOR, and p70 S6 kinase (S6K), suggesting that these molecules form a physical complex. Immunoprecipitates of Akt, Hsp90, mTOR, and S6K from IL-2-stimulated NK-92 cells contained telomerase activity. Furthermore, the findings that Hsp90 and mTOR immunoprecipitates from primary samples contained telomerase activity are consistent with the results from NK-92 cells. These results indicate that IL-2 stimulation induces hTERT activation and that the mechanism of IL-2-induced hTERT activation involves transcriptional or posttranslational regulation through the pathway including PI3K/Akt, Hsp90, mTOR, and S6K in NK cells.