Enhancement of antitumor natural killer cell activation by orally administered Spirulina extract in mice

Abstract

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-g and abolished in mice by treatment with asialoGM-1 but not CD8b 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-g 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. (Cancer Sci 2009; 100: 1494-1501)

Failure of mycoplasma lipoprotein MALP-2 to induce NK cell activation through dendritic cell TLR2

“…Previous reports suggested that TLR2 agonists have ability to induce NK activation (11,12). To investigate whether the mycoplasma lipopeptides harbor activity of NK cell activation, we added the Pam2Cys peptides (100 nM) to BMDC, NK cells or BMDC/NK co-culture as in a previous method assessing polyI:C activity for BMDC-mediated NK activation (10).…”

“…TLR3 and the adaptor TICAM-1 (TRIF) in mDC typically participate in driving NK activation in response to dsRNA (10). Recent studies on TLR2 agonists including lipopeptides also revealed that stimulation of TLR2 on mDC results in activation of the MyD88 pathway in mDC to drive external NK activation (11,12). NK cells play a role in early defense against various pathogens.…”

The beneficial effects of spirulina focusing on its immunomodulatory and antioxidant properties

“…was shown to induce an adjuvant effect along with BCG-cell wall skeleton to augment antitumor natural killer (NK) cell activation in mice. 21 Also, in similar studies, a significant reduction in the hepatic cytochrome P-450 content and …”

Extracts of Larix Leptolepis effectively augments the generation of tumor antigen-specific cytotoxic T lymphocytes via activation of dendritic cells in TLR-2 and TLR-4-dependent manner

“…TLR4, but not TLR2 use TRIF/TICAM pathway, which induces Type1 interferon as well as TLR3. Thus, TLR2 and TLR4 have been considered to act cooperatively when they recognize various ligands [38,47,48]. Therefore, it is possible to speculate that ELL partially stimulates innate immunity by two signal pathways mediated by TLR2 and TLR4.…”