Signaling pathway via TNF-α/NF-κB in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis
Signaling pathway via TNF-α/NF-κB in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis
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DOI：
10.1152/ajpgi.00071.2008
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发表时间：
2009-04-01
影响因子：
4.5
通讯作者：
Watanabe, Mamoru
中科院分区：
文献类型：
--
作者：
Onizawa, Michio;Nagaishi, Takashi;Watanabe, Mamoru
抗 TNF-α MAb 治疗已被认为是炎症性肠病 (IBD) 患者的成功维持治疗。此外，最近有报道称，阻断浸润造血细胞中的 TNF 受体 (TNFR) 1 信号传导可能会预防结肠炎相关癌症 (CAC) 的发展。然而，尚不清楚上皮细胞中的 TNF-α 信号传导是否参与 CAC 的发生。为了研究这一点，我们通过给予氧化偶氮甲烷 (AOM)，然后连续摄入右旋糖酐硫酸钠 (DSS)，研究了抗 TNF-α MAb 在 CAC 动物模型中的作用。我们观察到，DSS 给药小鼠的结肠上皮细胞中 NF-kappa B 通路被激活，与 TNFR2 而不是 TNFR1 的上调相关。免疫印迹分析还表明，与非肿瘤区域相比，在 AOM/DSS 给药小鼠诱导的 CAC 组织中，伴随 NF-κ B 激活的 TNFR2 上调更加复杂。 MP6-XT22（一种抗 TNF-α MAb）治疗可显着抑制上皮细胞中的此类 NF-κ B 活性。尽管无法减轻结肠炎的严重程度，但连续施用 MP6-XT22 减少了与 NF-κ B 失活相关的肿瘤数量和大小。综上所述，目前的研究表明，肠上皮细胞中的 TNFR2 信号传导可能直接参与持续性结肠炎 CAC 的发展，这意味着抗 TNF-α MAb 的维持治疗可能会预防长期 IBD 患者 CAC 的发展。
Treatment with anti-TNF-alpha MAb has been accepted as a successful maintenance therapy for patients with inflammatory bowel diseases (IBD). Moreover, it has been recently reported that blockade of TNF receptor (TNFR) 1 signaling in infiltrating hematopoietic cells may prevent the development of colitis-associated cancer (CAC). However, it remains unclear whether the TNF-alpha signaling in epithelial cells is involved in the development of CAC. To investigate this, we studied the effects of anti-TNF-alpha MAb in an animal model of CAC by administration of azoxymethane (AOM) followed by sequential dextran sodium sulfate (DSS) ingestion. We observed that the NF-kappa B pathway is activated in colonic epithelia from DSS-administered mice in association with upregulation of TNFR2 rather than TNFR1. Immunoblot analysis also revealed that the TNFR2 upregulation accompanied by the NF-kappa B activation is further complicated in CAC tissues induced in AOM/DSS-administered mice compared with the nontumor area. Such NF-kappa B activity in the epithelial cells is significantly suppressed by the treatment of MP6-XT22, an anti-TNF-alpha MAb. Despite inability to reduce the severity of colitis, sequential administration of MP6-XT22 reduced the numbers and size of tumors in association with the NF-kappa B inactivation. Taken together, present studies suggest that the TNFR2 signaling in intestinal epithelial cells may be directly involved in the development of CAC with persistent colitis and imply that the maintenance therapy with anti-TNF-alpha MAb may prevent the development of CAC in patients with long-standing IBD.