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Galectin-9 Induces Apoptosis Through the Calcium-Calpain-Caspase-1 Pathway¹

Yumiko Kashio^*, Kazuhiro Nakamura^*, Mohammad J. Abedin^*, Masako Seki^*,, Nozomu Nishi, Naoko Yoshida^*,, Takanori Nakamura and Mitsuomi Hirashima^2,*

Departments of ^* Immunology and Immunopathology, and Endocrinology, Kagawa Medical University, Ikenobe, Miki-cho, Kita-gun, Kagawa, Japan; and Research Division, GalPharma Co. Ltd., NEXT-Kagawa, Hayashi-cho, Takamatsu, Kagawa, Japan

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 -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 (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.

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