2013-01-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/681631摘要：介白質-6（IL - 6）是由日本大阪大學平野教授和岸本教授於1986 年發現，介白質-6 能刺激B細胞導引抗體的生產。隨後的研究顯示，介白質-6 藉由與膜結合的介白質-6 受體（古典的介白質-6 信號）或介白質-6 受體(-)/ gp130(+)的細胞通過可溶性介白質-6 受體（介白質-6 的反式信號）結合激活不同的細胞類型。功能上，介白質-6 是一個誘發合成急性相蛋白的重要因子，如C-反應蛋白，它血清中的含量在急性和慢性炎症性疾病中顯著升高。藉由活化 Jak/STAT-3 和RAS /ERK信號 / CEBP的途徑，介白質-6 的信號在控制分化和激活T淋巴細胞上扮演舉足輕重的作用。具體來說，介白質-6 與 TGF -β協同，誘導 Th17 細胞的生成，同時它抑制分化的調節性T細胞。因此，介白質-6 藉由調節性T細胞的反應被抑制，誘導一個炎症環境。因此，阻斷介白質-6 的信號已被證明是有效的方式用來治療類風濕關節炎，同時在自身免疫性疾病和炎症性疾病實驗模型，如慢性腸道炎症性疾病，糖尿病，炎症相關癌症，也被證明是有效的。重要的是，最近的進展進一步證實介白質-6 的反式信號(但不是介白質-6 古典信號)，是主要決定介白質-6 在體內調節急性炎症的方式。這些發現提出一個論點，就臨床應用前景而言，是否選擇性阻斷介白質-6 的反式信號，會是一個更具吸引力的和可行的治療標的。卵巢癌是婦科癌症致死的首要原因，其致死率在全球約從 50％至60％。目前絕大多數卵巢癌患者發現時屬晚期疾病，其治療是手術切除之後，接受紫杉和鉑為基礎的化療。儘管接受高度活性化療，晚期卵巢癌患者其疾病復發仍是一個主要問題，其中多數患者由於癌細胞獲得耐藥性終將死於這種疾病。在卵巢癌耐藥細胞，卵巢癌患者血清和腹水中，介白質-6 的含量皆顯著增加。前臨床研究結果支持抗介白質-6/抗介白質-6 受體治療策略在卵巢癌治療上是有希望的新方法。當卵巢癌進展到腹膜腔，腹膜和腸道漿膜的外觀有類似腹膜炎的發現。由於慢性炎症是參與腫瘤的進程，促進腫瘤的發展，其中一個最重要的環境因素，我們嘗試去揭露介白質-6 反式信號在卵巢癌進展的角色。我們最新的發現強烈支持這一觀點。我們發現，卵巢癌病人血清及腹水中可溶性介白質-6 受體是升高的。具有較高的可溶性介白質-6 受體的卵巢癌患者，也具有較高風險的疾病和較差的臨床療效。可溶性介白質-6 受體的存在使所有在卵巢癌腫瘤環境的細胞對介白質-6 反應。內皮細胞雖無介白質-6 受體仍可對介白質-6/介白質-6 受體複合體反應。介白質-6/可溶性介白質-6 受體複合體直接提高血管內皮細胞暴露於紫杉醇的存活比例，並調節內皮屏障通透性。sgp130Fc有效地抑制血管生成減少體內惡性腹水的形成。這些結果強調可溶性介白質-6 受體作為分子治療卵巢癌的標的。雖然我們是第一個證明了可溶性介白質-6 受體在卵巢癌致病角色的研究群，許多問題仍然懸而未決。此研究計畫項目啟動我們系統性研究介白質-6 反式信號與癌性腹膜炎，以及卵巢癌的進展的關連。這項計畫的研究成果將有助於我們了解介白質-6 反式信號在癌症生物學的角色，同時引領發展以介白質-6 的反式信號作為癌症治療的方向。<br> Abstract: Interleukin-6 (IL-6) was discovered in 1986 by Hirano and Kishimoto as a B cell stimulatory factor driving IgG production. Subsequent studies showed that IL-6 activates various cell types carrying the membrane bound IL-6R (classical IL-6 signaling) as well as IL-6R- gp130+ cells via the soluble IL-6R(IL-6 trans-signaling). Functionally, IL-6 is an important factor for the synthesis of acute phase proteins such as C-reactive protein, whose serum level is increased in acute and chronic inflammatory diseases. IL-6 signaling plays a pivotal role in controlling the differentiation and activation of T lymphocytes by inducing the Jak/STAT-3 and the Ras/ Erk/CEBP pathways. Specifically, IL-6 induces the generation ofTh17 cells together with TGF-β, while it inhibits differentiation of regulatory T cells. Therefore, IL-6promotes a proinflammatory milieu in which inducible Treg responses are suppressed. Accordingly, blockade of IL-6 signaling has been shown to be effective in treating rheumatoid arthritis and experimental models of autoimmune and chronic inflammatory diseases such as inflammatory bowel diseases, diabetes, as well as models of inflammation-associated cancer. Importantly, recent advances further verified that IL-6 trans-signaling, but not IL-6 classical signaling, is essentially responsible for the role of IL-6 in regulating acute inflammation in vivo. These findings raised the argument if selective blockade of IL-6 trans-signaling would be a more attractive and feasible therapeutic target in clinicalperspective. Ovarian cancer is the leading cause of gynecologic cancer deaths around the world, with the ratio of deaths to incidence ranging from 50% to 60%. Most ovarian cancer patients present with advanced disease, which is managed with surgical resection followed by taxane- and platinum-based chemotherapy. Despite receiving highly active chemotherapy, disease recurrence continues to be a major problem for advanced ovarian cancer patients as most of them will die of the disease due to the acquired drug resistance. IL-6 production is increased in drug resistant ovarian cancer cells, and in the serum and ascites of ovarian cancer patients. The results from preclinical studies supported that anti-IL-6/anti-IL-6R strategies would be promising novel approaches for therapy of ovarian cancer. When ovarian cancer advances into the peritoneal cavity, the peritoneum and the intestinal serosa may have a florid appearance similar to that found in peritonitis. As chronic inflammation is one of the most important environmental factors that participate in the neoplastic process, fostering tumor progression, we have aimed to unveil the role of IL-6 trans-signaling during ovarian cancer progression. Our latest findings strongly support this notion. We found that sIL-6Rα is present in high amounts in the ascites of patients with ovarian cancer. Patients with ovarian cancer who have elevated levels of sIL-6Rα at diagnosis also have features of highrisk disease and unfavorable clinical outcome. The presence of sIL-6Rα renders all cells responsive to IL-6 in the ovarian cancer tumor environment. Endothelial cells of the gp130+/IL-6Rα−/low phenotype respond to the designer cytokine Hyper IL-6. The IL-6/sIL-6Rα complex directly enhances survival/antiapoptosis of endothelial cells exposed to Taxol and modulates endothelial barrier permeability. The sgp130Fc effectively inhibits angiogenesis and malignant ascites formation in vivo. These findings highlighted sIL-6Rα as a molecular therapeutic target for ovarian cancer. Though we demonstrated for the first time the pathogenicity of sIL-6Rα in ovarian cancer, many questions remains unanswered. This project serves as the initiation of the systematical investigation of functional link between IL-6 trans-signaling and cancerous peritonitis as well as ovarian cancer progression. The results of this project will provide a better understanding of the role of IL-6 transsignaling in cancer biology, shed light on targeting IL-6 trans-signaling as an attractive target for cancer therapy.介白質-6卵巢癌介白質-6 的反式信號IL-6Ovarian cancerIL-6 transsignaling