Takahashi M, Ogasawara K, Takeda K, Hashimoto W, Sakihara H, Kumagai K, Anzai R, Satoh M, Seki S
Department of Oral Surgery, Tohku University School of Dentistry, Sendai, Japan.
J Immunol. 1996 Apr 1;156(7):2436-42.
We recently reported that systemic administration of IL-12 into mice activates NK1.1+ alpha beta T cells with intermediate TCR (NK1+TCRint) and induces strong MHC-unrestricted cytotoxicity in C57BL/6 mice. In the present report, we examined the effect of LPS on Kupffer cells and NK1+TCRint, cells in C57BL/6 mice. Administration of LPS, as well as synthetic lipid A analogue (ONO-4007), but not detoxified LPS, induces the increase of NK1 expression of NK1+TCRint cells (NKlhighTCRint) and the acquisition of strong MHC-unrestricted cytotoxicity of these cells against NK-sensitive and NK-resistant targets as does IL-12 administration. LPS as well as ONO-4007 induced IL-12 mRNA in hepatic mononuclear cells, mainly in plastic-adherent Kupffer cells. LPS-induced cytotoxicity of hepatic mononuclear cells was greatly reduced by in vivo injections of anti-IL-12 Ab, to a lesser extent by anti-IFN-gamma Ab, but not by anti-IL-1 nor anti-TNF-alpha Ab. Pretreatment of mice with LPS induced inhibition of hepatic metastases of i.v. injected EL4 cells in C57BL/6 euthymic and athymic mice and this antimetastasis was inhibited by injection of anti-IL-12 Ab. This antimetastatic effect of LPS in the liver was also observed in different strains of mice and tumors, In contrast to IL-12, however, LPS was not so effective when administered after tumor inoculation. These results revealed that LPS (lipid A) stimulates NK1+TCRint cells through IL-12 production from Kupffer cells and suggest that bacterial components, probably including those from intestine, are activators of Kupffer cells and NK1+TCRint, cells in the liver. It is also suggested that the host condition as well as LPS-induced cytokines other than IL-12 may affect antitumor effect induced by LPS in the liver.
我们最近报道，对小鼠进行白细胞介素-12（IL-12）的全身给药可激活具有中等亲和力T细胞受体（TCR）的NK1.1⁺αβT细胞（NK1⁺TCRint），并在C57BL/6小鼠中诱导强烈的主要组织相容性复合体（MHC）非限制性细胞毒性。在本报告中，我们研究了脂多糖（LPS）对C57BL/6小鼠库普弗细胞和NK1⁺TCRint细胞的影响。给予LPS以及合成脂多糖类似物（ONO-4007），而非解毒LPS，可诱导NK1⁺TCRint细胞（NKlhighTCRint）的NK1表达增加，并使其获得针对NK敏感和NK抗性靶标的强烈MHC非限制性细胞毒性，这与给予IL-12的效果相同。LPS以及ONO-4007可诱导肝单核细胞中IL-12信使核糖核酸（mRNA）的产生，主要是在贴壁的库普弗细胞中。体内注射抗IL-12抗体可使LPS诱导的肝单核细胞细胞毒性大幅降低，注射抗干扰素-γ（IFN-γ）抗体可使其在较小程度上降低，但注射抗IL-1抗体或抗肿瘤坏死因子-α（TNF-α）抗体则无此作用。用LPS预处理小鼠可抑制C57BL/6正常胸腺和无胸腺小鼠中静脉注射的EL4细胞的肝转移，而注射抗IL-12抗体可抑制这种抗转移作用。在不同品系的小鼠和肿瘤中也观察到了LPS在肝脏中的这种抗转移作用。然而，与IL-12不同的是，在肿瘤接种后给予LPS的效果并不那么显著。这些结果表明，LPS（脂多糖）通过库普弗细胞产生的IL-12刺激NK1⁺TCRint细胞，并提示细菌成分，可能包括来自肠道的那些成分，是肝脏中库普弗细胞和NK1⁺TCRint细胞的激活剂。还提示宿主状况以及LPS诱导的除IL-12之外的细胞因子可能会影响LPS在肝脏中诱导的抗肿瘤作用。
