IL-8 promotes cell proliferation and migration through metalloproteinase-cleavage proHB-EGF in human colon carcinoma cells
IL-8 promotes cell proliferation and migration through metalloproteinase-cleavage proHB-EGF in human colon carcinoma cells
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DOI：
10.1016/j.cyto.2004.11.005
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发表时间：
2005-03-21
期刊：
影响因子：
3.8
通讯作者：
Itoh, M
中科院分区：
文献类型：
--
作者：
Itoh, Y;Joh, T;Itoh, M
据报道，白细胞介素-8 （IL-8）在与g蛋白偶联受体（GPCR）家族成员结合后，可促进结肠癌细胞的肿瘤细胞生长。最近的研究表明，刺激GPCR可以通过激活崩解素和金属蛋白酶（ADAM）诱导表皮生长因子（EGF）配体的脱落，并随后激活EGF受体（EGFR）。在这项研究中，我们研究了IL-8在人结肠癌细胞系（Caco2）中促进细胞增殖和迁移的机制。IL-8以剂量依赖的方式增加Caco2的DNA合成，这被ADAM、EGFR激酶和MEK抑制剂抑制。IL-8在5-90分钟后瞬间诱导EGFR酪氨酸磷酸化，这被ADAM抑制剂完全抑制。作为EGFR关键配体的HB-EGF中和抗体也阻断了IL-8对EGFR的反式活化和细胞增殖。由于IL-8诱导的细胞迁移被ADAM抑制剂和HB-EGF中和抗体进一步抑制，我们的数据表明，IL-8通过ADAM依赖的途径诱导细胞增殖和迁移，HB-EGF作为该途径的主要配体起着重要作用。(c) 2005 Elsevier Ltd版权所有。
Interleukin-8 (IL-8) has been reported to promote tumor cell growth in colon cancer cells after binding to its receptors, which are members of the G-protein coupled receptor (GPCR) family. Recent studies demonstrated that stimulation of GPCR can induce shedding of epidermal growth factor (EGF) ligands via activation of a disintegrin and metalloprotease (ADAM), with subsequent transactivation of the EGF receptor (EGFR). In this study, we investigated mechanisms of cell proliferation and migration stimulated by IL-8 in a human colon carcinoma cell line (Caco2). IL-8 increased DNA synthesis of Caco2 in a dose dependent manner and this was inhibited by ADAM, EGFR kinase, and MEK inhibitors. IL-8 transiently induced EGFR tyrosine phosphorylation after 5-90 min and this was completely inhibited by ADAM inhibitor. Neutralizing antibody against HB-EGF as a key ligand for EGFR also blocked transactivation of EGFR and cell proliferation by IL-8. Since IL-8-induced cell migration was further suppressed by the ADAM inhibitor and the HB-EGF neutralizing antibody, our data indicate that IL-8 induces cell proliferation and migration by an ADAM-dependent pathway, and that HB-EGF plays an important role as the major ligand for this pathway. (c) 2005 Elsevier Ltd. All rights reserved.