IN VIVO STUDY OF POTENTIAL MECHANISMS OF MACROPHAGE REPOLARIZATION ON THE BACKGROUND OF TUMOR GROWTH.

N Fedosova, A Chumak, N Cheremshenko, O Karaman, T Symchych, I Voyeykova
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Abstract

Aim: To study the activity of antitumor immunity effectors and to analyze possible mechanisms of peritoneal Mph M1/M2 repolarization of Balb/c mice under the influence of lectin from B. subtilis IMV B-7724 in the dynamics of the model tumor growth.

Materials and methods: Studies were performed on Balb/c mice; Ehrlich adenocarcinoma (АСЕ) was used as an experimental tumor. Lectin from B. subtilis IMV B-7724 was administered to ACE-bearing mice at a dose of 1 mg/kg of body weight, 10 times. Immunological testing was performed on days 21 and 28 after tumor grafting. The functional activity of peritoneal macrophages (Mph), natural killer (NK) cells, cytotoxic lymphocytes (CTL), and cytokine levels (IFN-γ, IL-4) were studied by the standard methods. mRNA expression levels of transcription factors STAT-1, STAT-6, IRF5, and IRF4 in Mph were evaluated.

Results: The administration of lectin from B. subtilis IMV B-7724 to mice with solid ACE led to the preservation of the initial functional state of peritoneal Mph M1 during the experiment. The bacterial lectin ensured the preservation of the cytotoxic activity of CD8+ T-lymphocytes and a significant (p < 0.05) increase in the NK activity (by 2.7 times compared to the intact animals and by 12.9 times compared to the untreated mice). A strong positive correlation was noted between the levels of the functional activity of Mph and CD8+ T-lymphocytes of animals with tumors and the indices of the antitumor effectiveness of bacterial lectin. The indirect polarization of Mph was evidenced by a strong positive correlation between the level of the NO/Arg ratio (which characterizes the direction of Mph polarization) and the cytotoxic activity of CD8+ T-lymphocytes, NK cells, and the expression of STAT1/STAT6 (the 21st day) and IRF5/IRF4 (the 28th day).

Conclusion: In ACE-bearing mice, repolarization of the peritoneal Mph toward M1 can occur not only due to the direct action of bacterial lectin on the cellular receptors but also with the involvement of other effectors of antitumor immunity (NK cells, T-lymphocytes). The transcription factors of the STAT and IRF signaling pathways are involved in the polarization process.

在体内研究肿瘤生长背景下巨噬细胞再极化的潜在机制。
目的:研究抗肿瘤免疫效应因子的活性,并分析在枯草杆菌凝集素 IMV B-7724 影响下 Balb/c 小鼠腹膜 Mph M1/M2 复极化在模型肿瘤生长动态中的可能机制:研究对象为Balb/c小鼠;艾氏腺癌(АСЕ)被用作实验肿瘤。以每公斤体重 1 毫克的剂量向 ACE 小鼠注射来自枯草杆菌 IMV B-7724 的凝集素,共注射 10 次。在肿瘤移植后的第 21 天和第 28 天进行免疫测试。用标准方法研究了腹腔巨噬细胞(Mph)、自然杀伤细胞(NK)、细胞毒性淋巴细胞(CTL)的功能活性和细胞因子水平(IFN-γ、IL-4),并评估了Mph中转录因子STAT-1、STAT-6、IRF5和IRF4的mRNA表达水平:结果:给患有固体 ACE 的小鼠注射枯草杆菌 IMV B-7724 的凝集素后,腹膜 Mph M1 在实验过程中保持了最初的功能状态。细菌凝集素确保了 CD8+ T 淋巴细胞细胞毒性活性的保持和 NK 活性的显著提高(p < 0.05)(与完整的动物相比提高了 2.7 倍,与未处理的小鼠相比提高了 12.9 倍)。肿瘤动物的 Mph 和 CD8+ T 淋巴细胞的功能活性水平与细菌凝集素的抗肿瘤效果指数之间存在很强的正相关性。Mph的间接极化表现为NO/Arg比值(表征Mph极化的方向)与CD8+ T淋巴细胞、NK细胞的细胞毒性活性以及STAT1/STAT6(第21天)和IRF5/IRF4(第28天)的表达之间存在很强的正相关性:结论:在服用 ACE 的小鼠中,腹膜 Mph 向 M1 的再极化不仅是由于细菌凝集素对细胞受体的直接作用,还与其他抗肿瘤免疫效应因子(NK 细胞、T 淋巴细胞)的参与有关。STAT 和 IRF 信号通路的转录因子参与了极化过程。
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