The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer.
The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer.
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DOI：
10.1084/jem.20100050
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发表时间：
2010-05-10
期刊：
影响因子：
--
通讯作者：
Ting JP
中科院分区：
文献类型：
--
作者：
Allen IC;TeKippe EM;Woodford RM;Uronis JM;Holl EK;Rogers AB;Herfarth HH;Jobin C;Ting JP
结肠炎相关癌（CAC）是炎症性肠病的主要并发症。我们表明，在葡聚糖硫酸钠（DSS）和氧化偶氮甲烷+ DSS模型中，炎性小体的组分在急性和复发性结肠炎和CAC期间具有保护作用。缺乏炎性体衔接蛋白PYCARD（ASC）和半胱天冬酶-1的小鼠表现出增加的疾病结局、发病率、组织病理学和息肉形成。肿瘤负荷增加与肿瘤部位IL-1β和IL-18水平降低相关。为了破译参与结肠炎和CAC的核苷酸结合结构域，富含亮氨酸的重复序列（NLR）组分，我们评估了Nlrp 3和Nlrc 4缺陷小鼠。Nlrp 3 −/−小鼠显示急性和复发性结肠炎和CAC增加，尽管Nlrp 3 −/−小鼠的疾病结局不如Pycard−/−或Casp 1 −/−动物严重。与类似治疗的野生型动物相比，在Nlrc 4 −/−小鼠中未观察到疾病进展或结局的显著差异。骨髓重建实验表明，Nlrp 3基因的表达和功能，造血细胞，而不是肠上皮细胞或基质细胞，是负责防止增加肿瘤发生。这些数据表明，炎性小体作为结肠炎和CAC的衰减剂发挥作用。
Colitis-associated cancer (CAC) is a major complication of inflammatory bowel diseases. We show that components of the inflammasome are protective during acute and recurring colitis and CAC in the dextran sulfate sodium (DSS) and azoxymethane + DSS models. Mice lacking the inflammasome adaptor protein PYCARD (ASC) and caspase-1 demonstrate increased disease outcome, morbidity, histopathology, and polyp formation. The increased tumor burden is correlated with attenuated levels of IL-1β and IL-18 at the tumor site. To decipher the nucleotide-binding domain, leucine-rich-repeat-containing (NLR) component that is involved in colitis and CAC, we assessed Nlrp3 and Nlrc4 deficient mice. Nlrp3−/− mice showed an increase in acute and recurring colitis and CAC, although the disease outcome was less severe in Nlrp3−/− mice than in Pycard−/− or Casp1−/− animals. No significant differences were observed in disease progression or outcome in Nlrc4−/− mice compared with similarly treated wild-type animals. Bone marrow reconstitution experiments show that Nlrp3 gene expression and function in hematopoietic cells, rather than intestinal epithelial cells or stromal cells, is responsible for protection against increased tumorigenesis. These data suggest that the inflammasome functions as an attenuator of colitis and CAC.
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10.1152/ajpgi.00328.2004
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