The inhibition of malignant melanoma cell invasion of bone by the TLR7 agonist R848 is dependent upon pro-inflammatory cytokines produced by bone marrow macrophages
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Yoko Manome1,2, Dai Suzuki1, Ayako Mochizuki3, Emi Saito1,4, Kiyohito Sasa1, Kentaro Yoshimura1, Tomio Inoue3, Masamichi Takami5, Katsunori Inagaki4, Takahiro Funatsu2 and Ryutaro Kamijo1
1Departments of Biochemistry School of Dentistry, Showa University, Shinagawa, Tokyo, Japan
2Department of Special Needs Dentistry, Division of Dentistry for Persons with Disabilities, Showa University Dental Hospital, Shinagawa, Tokyo, Japan
3Departments of Oral Physiology School of Dentistry, Showa University, Shinagawa, Tokyo, Japan
4Department of Orthopedic Surgery School of Medicine, Showa University, Shinagawa, Tokyo, Japan
5Departments of Pharmacology School of Dentistry, Showa University, Shinagawa, Tokyo, Japan
Dai Suzuki, email: [email protected]
Keywords: bone invasion; bone marrow macrophage; cytokines; malignant melanoma; R848
Received: December 23, 2017 Accepted: June 12, 2018 Published: July 06, 2018
Distant metastasis remarkably worsens the prognoses of malignant melanoma patients. Toll-like receptors (TLRs) recognize molecules derived from many types of pathogens and activate the innate intravital immune system. In this study, we examined the effects of R848, a TLR7 ligand, on bone invasion by malignant melanoma cells. Mice underwent transplantation with cells of a malignant melanoma cell line B16F10, and were also administered R848 every three days. Hindlimbs were obtained 13 days after transplantation and invasion of bone marrow by B16F10 cells was evaluated. ELISA was used to determine the concentrations of cytokines in mouse serum and in the culture medium from bone marrow macrophages (BMMs) in the presence or absence of R848. In addition, MTS assays were used to examine the effects of media from BMM cultures on the proliferation of B16F10 cells. The rate of infiltration by B16F10 cells and the area of invasion were significantly reduced with R848 administration. Furthermore, serum levels of IL-6, IL-12, and IFN-γ were significantly increased in mice administered R848, with the same trend observed in the culture medium of BMMs treated with R848. In addition, B16F10 cell proliferation was suppressed by the addition of medium from cultured BMMs treated with R848. Neutralization by antibodies against IL-6, IL-12, and IFN-γ abrogated the suppression of proliferation of B16F10 cells by culture medium from BMMs treated with R848. Our results suggest that R848 drives the production of IL-6, IL-12, and IFN-γ in BMMs, which reduces proliferation and bone invasion by B16F10 cells.
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