Oral administration of poly-gamma-glutamate induces TLR4- and dendritic cell-dependent antitumor effect |
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Authors: | Tae-Young Lee Yang-Hyun Kim Sun-Woo Yoon Jai-Chul Choi Jai-Myung Yang Chul-Joong Kim John T Schiller Moon-Hee Sung Haryoung Poo |
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Institution: | (1) Mucosal Immunology Laboratory, BioNanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-806, Korea;(2) BioLeaders Corporation, Daejeon, Korea;(3) Department of Life Science, Sogang University, Seoul, Korea;(4) College of Veterinary Medicine, Chungnam National University, Daejeon, Korea;(5) Laboratory of Cellular Oncology National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA;(6) Department of Bio and Nanochemistry, Kookmin University, Seoul, Korea; |
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Abstract: | Previously, we reported that the oral administration of high molecular mass poly-γ-glutamate (γ-PGA) induced antitumor immunity
but the mechanism underlying this antitumor activity was not understood. In the present study, we found that application of
high molecular mass γ-PGA induced secretion of tumor necrosis factor (TNF)-α from the bone-marrow-derived macrophages of wild
type (C57BL/6 and C3H/HeN) and Toll-like receptor 2 knockout (TLR2−/−) mice, but not those of myeloid differentiation factor 88 knockout (MyD88−/−) and TLR4-defective mice (C3H/HeJ). Production of interferon (IFN)-γ-inducible protein 10 (IP-10) in response to treatment
with γ-PGA was almost abolished in C3H/HeJ mice. In contrast to LPS, γ-PGA induced productions of TNF-α and IP-10 could not
be blocked by polymyxin B. Furthermore, γ-PGA-induced interleukin-12 production was also impaired in immature dendritic cells
(iDCs) from MyD88−/− and C3H/HeJ mice. Downregulation of MyD88 and TLR4 expression using small interfering RNA (siRNA) significantly inhibited
γ-PGA-induced TNF-α secretion from the RAW264.7 cells. γ-PGA-mediated intracellular signaling was markedly inhibited in C3H/HeJ
cells. The antitumor effect of γ-PGA was completely abrogated in C3H/HeJ mice compared with control mice (C3H/HeN) but significant
antitumor effect was generated by the intratumoral administration of C3H/HeN mice-derived iDCs followed by 2,000 kDa γ-PGA
in C3H/HeJ. These findings strongly suggest that the antitumor activity of γ-PGA is mediated by TLR4.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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Keywords: | Poly-gamma-glutamate MyD88 TLR4 Anti-tumor effect Dendritic cell |
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