Down-regulation of the expression of cyclooxygenase-2 and prostaglandin E2 by interleukin-4 is mediated via a reduction in the expression of prostanoid EP4 receptors in HCA-7 human colon cancer cells
Down-regulation of the expression of cyclooxygenase-2 and prostaglandin E2 by interleukin-4 is mediated via a reduction in the expression of prostanoid EP4 receptors in HCA-7 human colon cancer cells
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DOI：
10.1016/j.ejphar.2022.174863
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发表时间：
2022-03-01
影响因子：
5
通讯作者：
Fujino，Hiromichi
中科院分区：
文献类型：
--
作者：
Kitagawa，Kana;Hamaguchi，Ayaka;Fujino，Hiromichi
慢性炎症性肠病（IBD）的特征是胃肠道的长期炎症，与结直肠癌的风险增加有关。最近的研究表明，IBD的病理是由分化的CD 4+幼稚辅助性T细胞介导的过度活化的免疫应答引起的，如Th 1和Th 17细胞，而不是Th 2细胞。人E型前列腺素4（EP 4）受体及其通路也与结直肠癌的早期发展阶段沿着前列腺素E2（PGE 2）和环氧合酶-2（COX-2）水平的增加有关，前列腺素E2和环氧合酶-2（COX-2）是结直肠癌发生的标志。在本研究中，我们使用计算机分析和药理学实验，我们证明了白细胞介素（IL）-4，一个标志性的细胞因子的Th 2，下调考克斯-2和PGE 2在人结肠癌细胞系，HCA-7的表达。这一结果可能归因于通过白细胞介素-4受体刺激的信号转导子和转录激活子6的激活，通过诱导缺氧诱导因子-1 α，减少前列腺素类EP 4受体的表达。然而，另一种主要的Th 2细胞因子IL-13对HCA-7细胞中考克斯-2或前列腺素类EP 4受体的表达没有影响。因此，而不是Th 1/Th 17细胞的过度活化，Th 2细胞的失活/下调，随后在IBD中IL-4的产生减少，可能在细胞的癌性转化中起作用，至少在前列腺素类EP 4受体过度活化的肿瘤发生中起作用。
Chronic inflammatory bowel disease (IBD), which is characterized by prolonged inflammation of the gastrointestinal tract is associated with an increased risk of colorectal cancer. Recent studies revealed that the pathology of IBD is caused by hyperactivated immune responses mediated by differentiated CD4+naïve helper T cells, such as Th1 and Th17 cells, but not Th2 cells. The human E-type prostanoid 4 (EP4) receptor and its pathways have also been implicated in and/or associated with the early developmental stages of colorectal cancer along with increases in the levels of prostaglandin E2(PGE2) and cyclooxygenase-2 (COX-2), the hallmarks of colorectal carcinogenesis. In the present study, using anin silicoanalysis and pharmacological experiments, we demonstrated that interleukin (IL)-4, a signature cytokine of Th2 cells, down-regulated the expression of COX-2 and PGE2in the human colon cancer cell line, HCA-7. This result may be attributed to a reduction in the expression of prostanoid EP4 receptors through the induction of hypoxia inducible factor-1α via the interleukin-4 receptor-stimulated activation of signal transducer and activator of transcription 6. However, another major Th2 cytokine IL-13 had no effect on the expression of COX-2 or prostanoid EP4 receptors in HCA-7 cells. Therefore, instead of the hyperactivation of Th1/Th17 cells, the deactivation/down-regulation of Th2 cells followed by a decrease in the production of IL-4 in IBD may play a role in the cancerous transformation of cells, at least in prostanoid EP4 receptor-overactivated tumorigenesis.