Interleukin-1β-driven inflammation promotes the development and invasiveness of chemical carcinogen-induced tumors
Interleukin-1β-driven inflammation promotes the development and invasiveness of chemical carcinogen-induced tumors
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DOI：
10.1158/0008-5472.can-06-2956
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发表时间：
2007-02-01
期刊：
影响因子：
11.2
通讯作者：
Apte, Ron N.
中科院分区：
文献类型：
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作者：
Krelin, Yakov;Voronov, Elena;Apte, Ron N.
在IL-1缺陷小鼠中评估了微环境白细胞介素1（IL-1）对3-甲基胆蒽（3-MCA）诱导的致癌作用，即，IL-1 β（-/-）、IL-1 α（-/-）、IL-1 α/β（-/-）-（双敲除）和缺乏天然存在的IL-1抑制剂、IL-1受体拮抗剂（IL-1 Ra）的小鼠。肿瘤在所有野生型（WT）小鼠中发展，而在IL-1 β缺陷小鼠中，肿瘤发展较慢，仅在一些小鼠中发展。在IL-1 Ra缺陷小鼠中，肿瘤发展最快。WT和IL-1 α缺陷小鼠的肿瘤发生率相似。组织学分析显示，纤维化结构在橄榄油中的致癌物液滴周围形成胶囊，类似于异物样肉芽肿，在注射3-MCA后10天出现，并持续至局部肿瘤发展。在IL-1 β缺陷小鼠中，在致癌物注射部位发现稀疏的白细胞浸润，而在IL-1 Ra缺陷小鼠中，观察到密集的嗜中性粒细胞浸润。用重组IL-1 Ra治疗IL-1 R α缺陷小鼠，但不使用肿瘤坏死因子抑制剂，可消除早期白细胞浸润。以巨噬细胞为主的晚期白细胞浸润（第70天）在WT和IL-1 α缺陷小鼠中也很明显，但在IL-1 β缺陷小鼠中几乎不存在。从IL-1 R α缺陷小鼠的3-MCA诱导肿瘤建立的纤维肉瘤细胞系比WT小鼠的细胞系更具侵袭性和转移性; IL-1缺陷小鼠的细胞系侵袭性最小。这些观察结果表明，微环境来源的IL-1 β，而不是IL-1 α，在化学致癌和确定恶性细胞的侵袭潜力的关键作用。
The role of microenvironment interleukin 1 (IL-1) on 3-methylcholanthrene (3-MCA)-induced carcinogenesis was assessed in IL-1-deficient mice, i.e., IL-1 beta(-/-), IL-1 alpha(-/-), IL-1 alpha/beta(-/-) - (double knockout), and mice deficient in the naturally occurring inhibitor of IL-1, the IL-1 receptor antagonist (IL-1Ra). Tumors developed in all wild-type (WT) mice, whereas in IL-1 beta-deficient mice, tumors developed slower and only in some of the mice. In IL-1Ra-deficient mice, tumor development was the most rapid. Tumor incidence was similar in WT and IL-1 alpha-deficient mice. Histologic analyses revealed fibrotic structures forming a capsule surrounding droplets of the carcinogen in olive oil, resembling foreign body-like granulomas, which appeared 10 days after injection of 3-MCA and persisted until the development of local tumors. A sparse leukocyte infiltrate was found at the site of carcinogen injection in IL-1 beta-deficient mice, whereas in IL-IRa-deficient mice, a dense neutrophilic infiltrate was observed. Treatment of IL-1R alpha-deficient mice with recombinant IL-1Ra but not with an inhibitor of tumor necrosis factor abrogated the early leukocytic infiltrate. The late leukocyte infiltrate (day 70), which was dominated by macrophages, was also apparent in WT and IL-1 alpha-deficient mice, but was nearly absent in IL-1 beta-deficient mice. Fibrosarcoma cell lines, established from 3-MCA-induced tumors from IL-1R alpha-deficient mice, were more aggressive and metastatic than lines from WT mice; cell lines from IL-1-deficient mice were the least invasive. These observations show the crucial role of microenvironment-derived IL-1 beta, rather than IL-1 alpha, in chemical carcinogenesis and in determining the invasive potential of malignant cells.