Leptin Receptor-Related Immune Response in Colorectal Tumors: The Role of Colonocytes and Interleukin-8
Leptin Receptor-Related Immune Response in Colorectal Tumors: The Role of Colonocytes and Interleukin-8
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DOI：
10.1158/0008-5472.can-08-1017
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发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Sobhani, Iradj
中科院分区：
文献类型：
--
作者：
Abolhassani, Mohammad;Aloulou, Nijez;Sobhani, Iradj
我们已经证明，瘦素受体ObRb在结直肠癌细胞中过度表达，这可能会影响患者的预后。我们研究了作为瘦素靶点的结肠细胞，并描述了它们在抗肿瘤免疫应答中的关键作用。通过靶向阵列测量HT 29细胞中的细胞因子和趋化因子mRNA。在体外，正常结肠细胞和人结肠癌细胞（HT 29、Caco-2、SW 480和HCT 116）被用于研究ObRb转导系统和细胞因子释放。用动物结肠细胞、CD 8脾细胞和来自献血员的人HT 29、HCT 116和CD 8（+）细胞研究了淋巴细胞对瘦素刺激的结肠细胞的反应。分别在雄性大鼠和裸鼠中测量瘦素诱导的正常结肠粘膜中的细胞因子释放和体内肿瘤生长和肿瘤内的细胞因子释放。通过Fisher精确检验和Mann-Whitney U检验进行统计分析。在正常和肿瘤结肠细胞中，通过增加核因子-κ B的活化，响应于瘦素产生各种细胞因子及其受体。白细胞介素-8（IL-8）是体外产生的主要细胞因子。IL-8及其受体CXCR 1在肿瘤组织中的表达水平高于正常粘膜组织。全身性瘦素增强正常结肠细胞和HT 29异种移植肿瘤结肠细胞中的促炎细胞因子。在体外，瘦素处理后的结肠细胞衍生产物刺激正常CD 8（+）T细胞中穿孔素和颗粒酶B的表达。瘦素通过直接刺激结肠细胞来触发肿瘤组织中的炎症反应，结肠细胞可以在肿瘤微环境中募集T细胞毒性细胞。[Cancer Res 2008;68（22）：9423-32]
We have shown that ObRb, the leptin receptor, is over-expressed in colorectal cancer cells, and that this may influence the patients' outcome. We investigated colonocytes as leptin targets and characterized their pivotal role in antitumor immune response. Cytokine and chemokine mRNAs in HT29 cells were measured by targeted arrays. In vitro, normal colonocytes and human colon cancer cells (HT29, Caco-2, SW480, and HCT116) were used to investigate ObRb transduction system and cytokine releases. Animal colonocytes and CD8 splenocytes and human HT29, HCT116, and CD8(+) cells from blood donors were used to investigate the lymphocyte response to the colonocytes when stimulated by leptin. Leptin-induced cytokine releases in the normal colonic mucosa and tumor growth and cytokine releases within tumors in vivo were measured in male rats and nude mice, respectively. Statistical analysis was done by Fisher's exact and Mann-Whitney U tests. Various cytokines and their receptors were produced in normal and tumoral colonocytes in response to leptin by increasing nuclear factor-kappa B activation. Interleukin-8 (IL-8) was the main cytokine produced in vitro. The levels of IL-8 and its receptor, CXCR1, were higher in tumors than in homologous normal mucosa. Systemic leptin enhanced the proinflammatory cytokines in normal colonocytes and in HT29 xenografted tumor colonocytes. Colonocyte-derived products after leptin treatment stimulated perforin and granzyme B expressions in normal CD8(+) T cells in vitro. Leptin triggers an inflammatory response in tumor tissue by directly stimulating colonocytes, which can recruit T cytotoxic cells in the tumor microenvironment. [Cancer Res 2008;68(22):9423-32]