Interleukin-11 - Biological activity and clinical studies
Interleukin-11 - Biological activity and clinical studies
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DOI：
10.2165/00063030-199708060-00002
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发表时间：
1997-12-01
期刊：
影响因子：
6.8
通讯作者：
Keith, JC
中科院分区：
文献类型：
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作者：
Dorner, AJ;Goldman, SJ;Keith, JC
白细胞介素-11 （IL-11）是一种与多种造血和非造血细胞相互作用的细胞因子。重组人IL-11 （rhIL-11; prerelvekin）是在大肠杆菌中产生的，与天然存在的蛋白质的不同之处在于没有氨基末端脯氨酸残基。与其他因子协同作用，rhIL-11在体外刺激髓系、红系和巨核细胞祖细胞的生长。在体内，rhIL-11在小鼠、大鼠、狗、豚鼠、仓鼠和非人类灵长类动物中具有活性，其主要活性测量是刺激巨核细胞生成和血小板生成。在两项临床试验中，rhIL-11通过显著减少化疗引起的严重血小板减少症显示出益处。除了其血小板生成活性外，rhIL-11还在急性胃肠道粘膜损伤模型中显示出活性，在细胞消融治疗后的小鼠中，rhIL-11提高了存活率，在化疗诱导的口腔粘膜炎仓鼠模型中，用rhIL-11治疗与减少粘膜损伤、加速愈合和减少死亡人数有关，目前，rhIL-11正在进行化疗诱导的粘膜炎治疗的临床试验。在急性结肠损伤和炎症性肠病大鼠模型中，rhIL-11治疗可减轻肠黏膜损伤，缓解临床症状。rhIL-11直接作用于活化的巨噬细胞，减少促炎介质的产生。在内毒素血症动物模型中，rhIL-11治疗可降低血清促炎细胞因子水平并阻断低血压。rhIL-11增加革兰氏阴性脓毒症和中毒性休克模型的存活率。基于这些研究，rhIL-11目前正处于治疗克罗恩病的临床试验中。正在进一步评估其他炎症情况。从机制上讲，rhIL-11在许多层面上起着控制炎症、改善组织损伤和维持创伤或感染时的止血作用。rhIL-11直接作用于肝细胞，诱导急性期反应物蛋白、血红素加氧酶和组织金属蛋白酶-1 （TIMP-1）的产生。rhIL-11也能诱导滑膜细胞和软骨细胞表达TIMP-1。给予rhIL-11与血浆血管性血友病因子和纤维蛋白原水平升高有关。rhIL-11治疗可能为癌症化疗患者提供多种益处，如预防血小板减少，胃肠道上皮保护和随后的粘膜炎减少，以及改善炎症并发症。此外，正在进一步评估rhIL-11在炎症性疾病（如炎症性肠病、类风湿性关节炎和败血症）治疗中的应用。
Interleukin-11 (IL-11) is a cytokine which interacts with a variety of haemopoietic and non-haemopoietic cell types. Recombinant human IL-11 (rhIL-11; oprelvekin) is produced in Escherichia coli and differs from the naturally occurring protein only in the absence of the amino-terminal proline residue.In synergy with other factors, rhIL-11 stimulates the growth of myeloid, erythroid, and megakaryocyte progenitor cells in vitro. In vivo, rhIL-11 is active in mice, rats, dogs, guinea pigs, hamsters and non-human primates, where the principal activity measured was stimulation of megakaryocytopoiesis and thrombopoiesis. rhIL-11 has shown benefit in 2 clinical trials by significantly reducing severe chemotherapy-induced thrombocytopenia.In addition to its thrombopoietic activity, rhIL-11 has also shown activity in models of acute gastrointestinal mucosal damage, rhIL-11 enhanced survival in mice following cytoablative therapy and in a hamster model of chemotherapy-induced oral mucositis, where treatment with rhIL-11 was associated with decreased mucosal damage, accelerated healing and reduced numbers of deaths, rhIL-11 is currently in clinical trials for the treatment of chemotherapy-induced mucositis.In rat models of acute colonic injury and inflammatory bowel disease, rhIL-11 treatment reduced intestinal mucosal damage and alleviated clinical signs. rhIL-11 has direct effects on activated macrophages to reduce the production of pro-inflammatory mediators. In animal models of endotoxaemia, rhIL-11 treatment reduced serum levels of pro-inflammatory cytokines and blocked hypotension. rhIL-11 increased survival in models of Gram-negative sepsis and toxic shock. Based on these studies, rhIL-11 is currently in clinical trials for treatment of Crohn's disease. Other inflammatory conditions are being further evaluated.Mechanistically, rhIL-11 functions at many levels to control inflammation, ameliorate tissue damage and maintain haemostasis in the face of trauma or infection. rhIL-11 has direct effects on hepatocytes, inducing the production of acute phase reactant proteins, haem oxygenase and tissue inhibitor of metalloproteinase-1 (TIMP-1). TIMP-1 expression can also be induced in synoviocytes and chondrocytes by treatment with rhIL-11. rhIL-11 administration has been associated with increased plasma levels of von Willebrand factor and fibrinogen.rhIL-11 treatment potentially offers multiple benefits for cancer chemotherapy patients, such as prevention of thrombocytopenia, gastrointestinal epithelial protection and subsequent reduction of mucositis, and amelioration of inflammatory complications. In addition, rhIL-11 is being evaluated further in the treatment of inflammatory disorders such as inflammatory bowel disease, rheumatoid arthritis and sepsis.