Hayakawa Y, Fujii H, Hase K, Ohnishi Y, Sakukawa R, Kadota S, Namba T, Saiki I
Department of Pathogenic Biochemistry, Research Institute for Wakan-Yaku, Toyama Medical and Pharmaceutical University, Japan.
Biol Pharm Bull. 1998 Nov;21(11):1154-9. doi: 10.1248/bpb.21.1154.
We have investigated the anti-metastatic effect of Celosia argentea seed extracts (CAE), which have traditionally been used as a therapeutic drug for eye and hepatic diseases in China and Japan. Intraperitoneal (i.p.) administration of CAE for 7 d before tumor inoculation significantly inhibited liver metastasis caused by intraportal injection of colon 26-L5 carcinoma cells in a dose-dependent manner. CAE also showed concentration dependent mitogenic activity on BALB/c whole splenocytes, whereas incubation of the non-adherent fraction of splenocytes with CAE did not induce this activity. CAE has the ability to induce interleukin (IL)-12 production from macrophages in vitro. Following i.p. administration of CAE the maximal levels of IL-12 and interferon (IFN)-gamma production in serum were achieved at 2-3 and 6 h, respectively. Experiments using macrophage- or NK cell-deficient mice revealed that CAE-induced IL-12 in serum was not mediated by macrophages and that IFN-gamma production was mainly dependent on natural killer (NK) cells. Since CAE was inactive when the contributions of macrophages were removed in our system, its inhibitory mechanism is likely to be mainly associated with the activation of macrophages to an anti-metastatic state rather than NK cells. CAE administration resulted in increased production of IL-2, IFN-gamma and decreased production of a Th2 cytokine (IL-4) from splenocytes stimulated by PMA and A23187. Thus, the anti-metastatic effect by CAE is based on its immunomodulating properties including induction of cytokines such as IL-12, IL-2 and IFN-gamma leading to a Th1 dominant immune state and activating macrophages to the tumoricidal state. This may provide a basis for the inhibition of cancer metastasis.
我们研究了青葙种子提取物（CAE）的抗转移作用，在中国和日本，青葙种子提取物传统上被用作治疗眼部和肝脏疾病的药物。在接种肿瘤前7天腹腔注射CAE，可显著抑制门静脉注射结肠26-L5癌细胞所致的肝转移，且呈剂量依赖性。CAE对BALB/c全脾细胞也表现出浓度依赖性的促有丝分裂活性，而用CAE孵育脾细胞的非贴壁部分则不会诱导这种活性。CAE在体外具有诱导巨噬细胞产生白细胞介素（IL）-12的能力。腹腔注射CAE后，血清中IL-12和干扰素（IFN）-γ的最大产生水平分别在2 - 3小时和6小时达到。使用巨噬细胞或自然杀伤（NK）细胞缺陷小鼠进行的实验表明，血清中CAE诱导产生的IL-12不是由巨噬细胞介导的，且IFN-γ的产生主要依赖于NK细胞。由于在我们的系统中去除巨噬细胞的作用后CAE无活性，其抑制机制可能主要与巨噬细胞激活至抗转移状态有关，而非NK细胞。给予CAE导致经佛波酯（PMA）和离子霉素（A23187）刺激的脾细胞中IL-2、IFN-γ的产生增加，Th2细胞因子（IL-4）的产生减少。因此，CAE的抗转移作用基于其免疫调节特性，包括诱导细胞因子如IL-12、IL-2和IFN-γ，从而导致Th1主导的免疫状态，并将巨噬细胞激活至杀肿瘤状态。这可能为抑制癌症转移提供依据。
