Oral administration of poly-gamma-glutamate induces TLR4- and dendritic cell-dependent antitumor effect = TLR4와 수지상세포에 의존적인 폴리감마글루탐산 경구투여에 의한 항암효과

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Title
Oral administration of poly-gamma-glutamate induces TLR4- and dendritic cell-dependent antitumor effect = TLR4와 수지상세포에 의존적인 폴리감마글루탐산 경구투여에 의한 항암효과
Author(s)
Tae Young Lee; Y H Kim; Sun Woo Yoon; J C Choi; J M Yang; C J Kim; J T Schiller; M H Sung; Haryoung Poo
Bibliographic Citation
Cancer Immunology Immunotherapy, vol. 58, no. 11, pp. 1781-1794
Publication Year
2009
Abstract
Previously, we reported that the oral administration of high molecular mass poly-gamma-glutamate (gamma-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 gamma-PGA induced secretion of tumor necrosis factor (TNF)-alpha 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)-gamma-inducible protein 10 (IP-10) in response to treatment with gamma-PGA was almost abolished in C3H/HeJ mice. In contrast to LPS, gamma-PGA induced productions of TNF-alpha and IP-10 could not be blocked by polymyxin B. Furthermore, gamma-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 gamma-PGA-induced TNF-alpha secretion from the RAW264.7 cells. Gamma-PGA-mediated intracellular signaling was markedly inhibited in C3H/HeJ cells. The antitumor effect of gamma-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 gamma-PGA in C3H/HeJ. These findings strongly suggest that the antitumor activity of gamma-PGA is mediated by TLR4.
Keyword
Poly-gamma-glutamateMyD88TLR4Anti-tumor eVectDendritic cell
ISSN
0340-7004
Publisher
Springer
DOI
http://dx.doi.org/10.1007/s00262-009-0689-4
Type
Article
Appears in Collections:
Division of Research on National Challenges > Infectious Disease Research Center > 1. Journal Articles
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