Quiniou Christiane, Kooli Emna, Joyal Jean-Sébastien, Sapieha Przemyslaw, Sennlaub Florian, Lahaie Isabelle, Shao Zhuo, Hou Xin, Hardy Pierre, Lubell William, Chemtob Sylvain
Department of Pediatrics and Pharmacology, Hôpital Ste Justine, Research Center, Montreal, Quebec, CA.
Semin Perinatol. 2008 Oct;32(5):325-33. doi: 10.1053/j.semperi.2008.07.001.
Inflammation participates in the genesis and progression of hypoxic-ischemic brain injury. Interleukin (IL)-1 is a major pro-inflammatory cytokine, which plays a dominant role in hypoxic-ischemic (and postinfectious) brain damage. Abundant evidence reveals the principal involvement of IL-1 over other pro-inflammatory cytokines. IL-1 interacts with the IL-1 receptor I (IL-1RI). The natural IL-1 receptor antagonist (IL-1ra) is a large 17.5-kDa peptide that competes with IL-1 for its binding site on IL-1RI. Recombinant IL-1ra (Kineret) is effective in human inflammatory conditions. However, a number of drawbacks of IL-1ra limit its broader use; these include injection site reactions [70%], broad immunosuppression, and high costs. We hereby report the characterization of a small (peptide) IL-1RI antagonist we developed, namely rytvela (termed 101.10), and its efficacy in models of (gut) inflammation and of newborn hypoxic-ischemic brain injury. Experiments reveal that 101.10 is selective for the IL-1RI and inhibits to a variable extent different effects induced by IL-1. 101.10 is effective in vivo (on systemic as well as oral administration) in established models of inflammation involving IL-1, notably in inflammatory bowel disease, and is superior to dexamethasone. In a rat pup model of hypoxic-ischemic brain injury (Rice-Vannucci model), where IL-1 and IL-1R expression is increased, 101.10 preserved microvascular density, parenchymal integrity, and brain mass. In conclusion, we hereby describe for the first time the discovery of a stable, potent, and effective specific IL-1RI small (peptide) antagonist, namely 101.10 (rytvela), which exhibits allosteric modulatory properties, and is effective in vivo in models of inflammation (known to involve IL-1) and in particular in hypoxic-ischemic newborn brain injury. 101.10 (and small alike compounds) may be suitable alternatives to IL-1ra.
炎症参与缺氧缺血性脑损伤的发生和发展。白细胞介素（IL）-1是一种主要的促炎细胞因子，在缺氧缺血性（和感染后）脑损伤中起主导作用。大量证据表明，与其他促炎细胞因子相比，IL-1起主要作用。IL-1与IL-1受体I（IL-1RI）相互作用。天然的IL-1受体拮抗剂（IL-1ra）是一种17.5 kDa的大分子肽，它与IL-1竞争其在IL-1RI上的结合位点。重组IL-1ra（凯奈立）在人类炎症性疾病中有效。然而，IL-1ra的一些缺点限制了其更广泛的应用；这些缺点包括注射部位反应[70%]、广泛的免疫抑制和高成本。我们在此报告我们开发的一种小（肽）IL-1RI拮抗剂即rytvela（称为101.10）的特性及其在（肠道）炎症模型和新生儿缺氧缺血性脑损伤模型中的疗效。实验表明，101.10对IL-1RI具有选择性，并在不同程度上抑制IL-1诱导的不同效应。101.10在涉及IL-1的已建立的炎症模型中（无论是全身给药还是口服给药）在体内均有效，尤其是在炎症性肠病中，并且优于地塞米松。在缺氧缺血性脑损伤的大鼠幼崽模型（赖斯 - 万努奇模型）中，IL-1和IL-1R表达增加，101.10可保持微血管密度、实质完整性和脑质量。总之，我们首次在此描述了一种稳定、强效且有效的特异性IL-1RI小（肽）拮抗剂即101.10（rytvela）的发现，它具有变构调节特性，并且在炎症模型（已知涉及IL-1）尤其是新生儿缺氧缺血性脑损伤模型中在体内有效。101.10（以及类似的小分子化合物）可能是IL-1ra的合适替代物。
