Galectin-9 induces apoptosis through the calcium-calpain-caspase-1 pathway

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-LEHD-FMK (caspase-9 inhibitor), and Z-AEVD-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 (CA(2+)) influx, and that either the intracellular CA(2+) 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 CA(2+)-calpain-caspase-1 pathway, and that Gal-9 plays a role in immunomodulation of T cell-mediated immune responses.