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.
Kashio
Yumiko
Y
Department of Immunology and Immunopathology, Kagawa Medical University, Ikenobe, Miki-cho, Kita-gun, Kagawa, Japan.
Nakamura
Kazuhiro
K
Abedin
Mohammad J
MJ
Seki
Masako
M
Nishi
Nozomu
N
Yoshida
Naoko
N
Nakamura
Takanori
T
Hirashima
Mitsuomi
M
D000276:Adjuvants, Immunologic / Q000502:physiology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D002154:Calpain / Q000502:physiology*; D020170:Caspase 1 / Q000502:physiology*; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D037161:Galectins / Q000502:physiology*; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D009000:Monocytes / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D022423:Myeloid Cells / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D037161:Galectins; C105032:LGALS9 protein, human; D009842:Oligopeptides; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D002154:Calpain; D020170:Caspase 1; D002118:Calcium