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01-11-2009 | Original Article

Oral administration of poly-gamma-glutamate induces TLR4- and dendritic cell-dependent antitumor effect

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

Published in: Cancer Immunology, Immunotherapy | Issue 11/2009

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.

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Title: Oral administration of poly-gamma-glutamate induces TLR4- and dendritic cell-dependent antitumor effect
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
Publication date: 01-11-2009
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 11/2009
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-009-0689-4

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