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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Colon carcinoma cell interaction with liver sinusoidal endothelium inhibits organ-specific antitumor immunity through interleukin-1-induced mannose receptor in mice.
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Colon carcinoma cell interaction with liver sinusoidal endothelium inhibits organ-specific antitumor immunity through interleukin-1-induced mannose receptor in mice.

机译：结肠癌细胞与肝窦内皮细胞的相互作用通过白介素1诱导的小鼠甘露糖受体抑制器官特异性抗肿瘤免疫力。

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摘要

Mannose receptor (ManR)-mediated liver sinusoidal endothelial cell (LSEC) endocytosis plays a role in antigen presentation and innate immunity, but its role in hepatic metastasis is unknown. We studied ManR-mediated endocytosis during C26 colorectal cancer cell interaction with LSECs and its implications in metastasis. Uptake of labeled ManR ligands (mannan and ovalbumin) and immunohistochemistry were used to study ManR endocytosis and expression. Several interleukin (IL)-1 inhibitors and the cyclooxygenase-2 (COX-2) inhibitor celecoxib were used to analyze the role of IL-1 and COX-2 in ManR regulation. Anti-mouse ManR antibodies and ManR knockout (ManR(-/-)) mice were used to identify ManR-dependent mechanisms during antitumor immune response of liver sinusoidal lymphocytes (LSLs) interacting with tumor-activated LSECs. ManR expression and endocytosis increased in tumor-activated LSECs through a two-step mechanism: (1) Release of COX-2-dependent IL-1-stimulating factors by lymphocyte function-associated antigen-1-expressing C26 cells in response to intercellular adhesion molecule-1 (ICAM-1), which was expressed and secreted by tumor-activated LSECs; and (2) widespread up-regulation of ManR in LSECs through tumor-induced IL-1. In addition, LSLs that had interacted with tumor-activated LSECs in vivo decreased their antitumor cytotoxicity and interferon (IFN)-gamma secretion while they increased IL-10 release ex vivo. IFN-gamma/IL-10 ratio also decreased in the hepatic blood from tumor-injected mice. Immunosuppressant effects of tumor-activated LSECs on LSLs were abrogated in both LSECs from ManR(-/-) mice and tumor-activated LSECs given anti-mouse ManR antibodies. CONCLUSION: ICAM-1-induced tumor COX-2 decreased antitumor activity during hepatic metastasis through IL-1-induced ManR. ManR constituted a common mediator for prometastatic effects of IL-1, COX-2, and ICAM-1. A rise in hepatic IFN-gamma/IL-10 ratio and antitumor cytotoxicity by way of ManR blockade is consistent with the antimetastatic effects of IL-1, COX-2, and ICAM-1 inhibitors. These data support ManR and ManR-stimulating factors as targets for hepatic colorectal metastasis therapy.
机译：甘露糖受体（ManR）介导的肝窦内皮细胞（LSEC）内吞作用在抗原呈递和先天免疫中起作用，但其在肝转移中的作用尚不清楚。我们研究了C26大肠癌细胞与LSEC相互作用期间ManR介导的内吞作用及其在转移中的意义。摄取标记的ManR配体（甘露聚糖和卵清蛋白）和免疫组化研究了ManR的内吞作用和表达。几种白介素（IL）-1抑制剂和环氧合酶2（COX-2）抑制剂塞来昔布用于分析IL-1和COX-2在ManR调节中的作用。抗小鼠ManR抗体和ManR基因敲除（ManR（-/-））小鼠用于鉴定与肿瘤激活的LSEC相互作用的肝窦淋巴细胞（LSL）的抗肿瘤免疫应答过程中的ManR依赖性机制。在肿瘤激活的LSEC中，ManR表达和内吞作用通过两步机制增加：（1）淋巴细胞功能相关的表达抗原1的C26细胞响应细胞间粘附而释放COX-2依赖性IL-1刺激因子。通过肿瘤激活的LSECs表达和分泌的molecular-1（ICAM-1）; （2）通过肿瘤诱导的IL-1，LSEC中ManR普遍上调。此外，在体内与肿瘤激活的LSEC相互作用的LSL降低了其抗肿瘤细胞毒性和干扰素（IFN）-γ分泌，同时增加了离体的IL-10释放。注射了肿瘤的小鼠的肝血中IFN-γ/ IL-10的比例也降低了。在来自ManR（-/-）小鼠的LSEC和给予抗小鼠ManR抗体的肿瘤激活的LSEC中，肿瘤激活的LSEC对LSL的免疫抑制作用均被取消。结论：ICAM-1诱导的肿瘤COX-2通过IL-1诱导的ManR降低了肝转移过程中的抗肿瘤活性。 ManR构成了IL-1，COX-2和ICAM-1的促转移作用的通用介体。通过ManR阻断使肝IFN-γ/ IL-10比例增加和抗肿瘤细胞毒性与IL-1，COX-2和ICAM-1抑制剂的抗转移作用一致。这些数据支持ManR和ManR刺激因子作为肝结直肠转移治疗的靶标。

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