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通过阻断多种疾病中的白介素1来治疗炎症
Nat Rev Drug Discov.
2012 Aug.
免费PMC文章
Abstract
白介素1（IL-1）是一种高度活跃的促炎细胞因子，可降低疼痛阈值并损害组织。自身炎症综合征中IL-1活性阻断IL-1活性的单一疗法导致疾病严重程度的迅速持续降低，包括炎症介导的视力丧失，听力和器官功能的逆转。因此，这种方法可以有效地治疗常见疾病，例如炎后心力衰竭，并且针对广泛的新指示的试验正在进行中。到目前为止，已经批准了三种IL-1靶向剂：IL-1受体拮抗剂Anakinra，可溶性诱饵受体rilonacept和中和单克隆抗元素抗IL-1β抗体canakinumab。此外，在临床试验中，针对IL-1受体和中和抗IL-1α抗体的单克隆抗体和中和抗IL-1α抗体。
Conflict of interest statement
The authors declare no competing financial interests.
Figures
Step 1: in the necrotic area, dying cells lose membrane integrity. Step 2: dying cells release their contents, including the interleukin-1α (IL-1α) precursor. Anti-IL-1α antibodies neutralize IL-1α at this step. Step 3: IL-1α binds to IL-1 receptor type I (IL-1RI) on nearby resident fibroblasts, epithelial cells or in brain astrocytes, releasing chemokines and establishing a chemokine gradient. Anakinra or anti-IL-1RI antibodies block this step. The chemokine gradient facilitates the passage of blood neutrophils into the ischaemic area. Step 4: capillaries in the ischaemic tissues express intercellular adhesion molecule 1 (ICAM1). Circulating blood neutrophils roll on the endothelium, adhere to ICAM1 and enter the ischaemic tissue via diapedesis. Step 5: the number of neutrophils in the area of the necrotic event increases; the presence of local IL-1 prolongs the survival of neutrophils at this step. Step 6: neutrophil proteases cleave the extracellular IL-1α precursor into mature, more active forms. Step 7: neutrophils scavenge dying cells and release proteases that contribute to the destruction of penumbral cells.
Step 1: following an ischaemic event, cells undergo hypoxic damage, lose membrane integrity and the dying cell releases cell contents (see FIG. 1). Step 2: the preformed interleukin-1α (IL-1α) precursor is released. Anti-IL-1α antibodies neutralize IL-1α at this step. Step 3: IL-1α binds to IL-1 receptor type I (IL-1RI) on nearby resident macrophages. Anakinra or anti-IL-1RI antibodies prevent IL-1α activity at this step. Step 4: triggered by the binding of IL-1α to IL-1RI, resident macrophages synthesize inflammatory genes as well as the IL-1β precursor. Step 5: the IL-1β precursor undergoes intracellular processing by caspase 1. Caspase 1 inhibitors prevent the processing of IL-1β at this step. Step 6 involves the secretion of active IL-1β. Rilonacept or antibodies of IL-1β neutralize IL-1β in the extracellular compartment at this step. Step 7: with the breakdown of vascular integrity in the necrotic area, IL-1β gains access to the vascular compartment. Step 8: IL-1β binds to IL-1RI on capillaries and induces vascular cell adhesion molecule 1 (VCAM1). Step 9: blood monocytes roll along the endothelium and bind to VCAM1, followed by their migration into the ischaemic tissue via diapedesis. Increasing numbers of monocytes become a source of increased production of IL-1β. Step 10: opening of the endothelial junction results in capillary leak, with the passage of plasma proteins into the ischaemic area. Step 11: platelet-derived IL-1α binds to the endothelial IL-1RI and induces the expression of intercellular adhesion molecule 1 (ICAM1). Step 12: large numbers of neutrophils enter the tissue space and the presence of local IL-1 prolongs the survival of neutrophils. Step 13: neutrophil proteases are released. Step 14: the IL-1β precursor released into the extracellular space is cleaved by serine proteases to generate active IL-1β. Natural inhibitors of serine proteases such as α1 antitrypsin prevent the extracellular processing of the IL-1β precursor. Step 15: increasing numbers of neutrophils surround the necrotic area, scavenging dead cells and debris. Damaging neutrophilic proteases attack and injure penumbral cells, resulting in increased loss of function of the organ undergoing the ischaemic event. Blocking IL-1 cannot restore the necrotic tissue but reduces the loss of penumbral cells.
各种疾病中的IL-1阻滞剂指出，时间轴突出了白细胞介素-1（IL-1）覆盖剂在各种但并非所有适应症中的测试。AOSD，成人发病的疾病；Cantos，canakinumab抗炎血栓形成结果研究；帽，冷冻蛋白相关的周期综合征；FMF，家族性地中海热；HIDS，Hyper-IGD综合征；MWS，Muckle – Wells综合征；SJIA，全身少年特发性关节炎；STEMI，ST段海拔心肌梗塞；陷阱，TNF受体相关的周期综合征。
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