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Poly‐gamma‐glutamate induced antitumor immunity is toll‐like receptor 4 dependent

Previously, we reported that the oral administration of high molecular mass poly‐γ–glutamate (γ‐PGA) isolated from Bacillus subtilis sp. Chungkookjang induced antitumor immunity by activating natural killer (NK) cells but the molecular 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)‐ 2 αfrom the bone‐marrow‐derived macrophages (BMDMs) of wild type mice (C57BL/6 and C3H/HeN), but not those of myeloid differentiation factor 88 (MyD88)‐deficient mice (MyD88−/−) and Toll‐like receptor (TLR) 4‐defective mice (C3H/HeJ). Production of interferon (IFN)‐ 1 γ‐inducible protein 10 (IP‐10) in response to treatment with γ‐PGA was seen in macrophages from MyD88−/−and C3H/HeN mice, but was almost abolished in C3H/HeJ mice. In contrast to LPS, γ‐PGA induced productions of TNF and IP‐10 could not be blocked by polymyxin B. Furthermore, γ‐PGA‐induced Interleukin‐12 (IL‐12) production was also impaired in immature dendritic cells (iDCs) from MyD88−/− and C3H/HeJ mice. γ‐PGA‐mediated intracellular signaling, such as the activations of c‐Jun N‐terminal kinase (JNK), p38 kinase, nuclear factor (NF)‐ 1 κB, and interferon regulatory factor‐3 (IRF3) were markedly inhibited in C3H/HeJ cells. Furthermore, the antitumor effect of γ‐PGA was completely abrogated in C3H/HeJ mice compared with control mice (C3H/HeN). These findings strongly suggest that the antitumor activity of γ‐PGA is mediated by TLR4.