Galectin-9 induces apoptosis through the calcium-calpain-caspase-1 pathway
Galectin-9 induces apoptosis through the calcium-calpain-caspase-1 pathway
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DOI：
10.4049/jimmunol.170.7.3631
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发表时间：
2003-04-01
影响因子：
4.4
通讯作者：
Hirashima, M
中科院分区：
文献类型：
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作者：
Kashio, Y;Nakamura, K;Hirashima, M
半乳糖凝集素-9（Galectin-9，Gal-9）不仅诱导T细胞系的凋亡，而且以剂量和时间依赖性方式诱导其他类型的细胞系的凋亡。细胞凋亡被乳糖抑制，但不被蔗糖，表明β-半乳糖苷结合是必不可少的半乳糖-9诱导的细胞凋亡。此外，Gal-9需要至少60分钟的Gal-9结合和可能的从头蛋白合成来介导凋亡。我们还通过Gal-9评估了外周血T细胞的凋亡。活化的CD 4（+）和CD 8（+）T细胞均可诱导凋亡，但前者较后者更易发生凋亡。泛半胱天冬酶抑制剂（Z-VAD-FMK）抑制Gal-9诱导的细胞凋亡。此外，半胱天冬酶-1抑制剂（Z-YVAD-FMK），而不是其它抑制剂如Z-IETD-FMK（半胱天冬酶-8抑制剂）、Z-LEND-FMK（半胱天冬酶-9抑制剂）和Z-REVD-FMK（半胱天冬酶-10抑制剂），抑制Gal-9诱导的细胞凋亡。我们还发现钙蛋白酶抑制剂（Z-LLY-FMK）抑制Gal-9诱导的细胞凋亡，Gal-9诱导钙（Ca 2+）内流，并且细胞内Ca 2+螯合剂BAPTA-AM或肌醇三磷酸抑制剂2-氨基乙氧基二苯基硼酸酯抑制Gal-9诱导的细胞凋亡。这些结果表明，Gal-9通过Ca 2 +-钙蛋白酶-半胱天冬酶-1途径诱导细胞凋亡，并且Gal-9在T细胞介导的免疫应答的免疫调节中起作用。
Galectin-9 (Gal-9) induced the apoptosis of not only T cell lines but also of other types of cell lines in a dose- and time-dependent manner. The apoptosis was suppressed by lactose, but not by sucrose, indicating that beta-galactoside binding is essential for Gal-9-induced apoptosis. Moreover, Gal-9 required at least 60 min of Gal-9 binding and possibly de novo protein synthesis to mediate the apoptosis. We also assessed the apoptosis of peripheral blood T cells by Gal-9. Apoptosis was induced in both activated CD4(+) and CD8(+) T cells, but the former were more susceptible than the latter. A pan-caspase inhibitor (Z-VAD-FMK) inhibited Gal-9-induced apoptosis. Furthermore, a caspase-1 inhibitor (Z-YVAD-FMK), but not others such as Z-IETD-FMK (caspase-8 inhibitor), Z-LEND-FMK (caspase-9 inhibitor), and Z-REVD-FMK (caspase-10 inhibitor), inhibited Gal-9-induced apoptosis. We also found that a calpain inhibitor (Z-LLY-FMK) suppresses Gal-9-induced apoptosis, that Gal-9 induces calcium (Ca2+) influx, and that either the intracellular Ca2+ chelator BAPTA-AM or an inositol trisphosphate inhibitor 2-aminoethoxydiphenyl borate inhibits Gal-9-induced apoptosis. These results suggest that Gal-9 induces apoptosis via the Ca2+-calpain-caspase-1 pathway, and that Gal-9 plays a role in immunomodulation of T cell-mediated immune responses.