Enhancement of antitumor natural killer cell activation by orally administered Spirulina extract in mice.
Oral administration of hot-water extract of Spirulina, cyanobacterium Spirulina platensis, leads to augmentation of NK cytotoxicity in humans. Here, we applied to syngeneic tumor-implant mice (C57BL/6 versus B16 melanoma) Spirulina to elucidate the mechanism of raising antitumor NK activation. A B16D8 subcell line barely expressed MHC class I but about 50% expressed Rae-1, a ligand for NK activation receptor NKG2D. The Rae-1-positive population of implant B16 melanoma was effectively eliminated in the tumor mass progressed in mice. This antitumor activity was induced in parallel with IFN-gamma and abolished in mice by treatment with asialoGM-1 but not CD8beta Ab, suggesting the effector is NK cell. NK cell activation occurred in the spleen of wild-type mice medicated with Spirulina. This Spirulina-mediated enhanced NK activation was abrogated in MyD88 -/- mice but not in TICAM-1 -/- mice. The NK activating properties of Spirulina depending on MyD88 were confirmed with in vitro bone marrow-derived dendritic cells expressing TLR2/4. In D16D8 tumor challenge studies, the antitumor effect of Spirulina was abolished in MyD88 -/- mice. Hence, orally administered Spirulina enhances tumoricidal NK activation through the MyD88 pathway. Spirulina exerted a synergistic antitumor activity with BCG-cell wall skeleton, which is known to activate the MyD88 pathway via TLR2/4 with no NK enhancing activity. Spirulina and BCG-cell wall skeleton synergistically augmented IFN-gamma production and antitumor potential in the B16D8 versus C57BL/6 system. We infer from these results that NK activation by Spirulina has some advantage in combinational use with BCG-cell wall skeleton for developing adjuvant-based antitumor immunotherapy.
Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku Sapporo 060-8638, Japan.
Yuusuke
Y
Akao
Takashi
T
Ebihara
Hisayo
H
Masuda
Yoshiko
Y
Saeki
Takashi
T
Akazawa
Kaoru
K
Hazeki
Osamu
O
Hazeki
Misako
M
Matsumoto
Tsukasa
T
Seya
D000276:Adjuvants, Immunologic / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001500:BCG Vaccine / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002473:Cell Wall / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004357:Drug Synergism; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology; D011208:Powders; D013047:Specific Pathogen-Free Organisms; D053545:Spirulina / Q000276:immunology*; D013154:Spleen / Q000166:cytology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D053594:Myeloid Differentiation Factor 88; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011208:Powders; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D007371:Interferon-gamma