Department of Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Ann Rheum Dis. 2010 Dec;69(12):2204-12. doi: 10.1136/ard.2009.127241. Epub 2010 Aug 2.
Interleukin 18 (IL-18) is a novel mediator of angiogenesis in rheumatoid arthritis (RA).
To examine the role of IL-18 in RA angiogenesis and the signalling mechanisms involved.
Human dermal microvascular endothelial cell (HMVEC) chemotaxis, capillary morphogenesis assays and Matrigel plug angiogenesis assays were performed in vivo using IL-18 with or without signalling inhibitors. A novel model of angiogenesis was devised using dye-tagged HMVECs to study their homing into RA and normal (NL) synovial tissues (STs) engrafted in severe combined immunodeficient (SCID) mice.
IL-18-mediated angiogenesis depended on Src and Jnk, as the inhibitors of Src and Jnk blocked IL-18-induced HMVEC chemotaxis, tube formation and angiogenesis in Matrigel plugs. However, inhibitors of Janus kinase 2, p38, MEK, phosphatidylinositol-3-kinase and neutralising antibodies to vascular endothelial growth factor or stromal derived factor-1α did not alter IL-18-induced HMVEC migration. These results were confirmed with Jnk or Src sense or antisense oligodeoxynucleotides. Moreover, IL-18 induced phosphorylation of Src and Jnk in HMVECs. As proof of principle, IL-18 null mice had a significantly decreased angiogenesis compared with wild-type mice in Matrigel plug angiogenesis assays in vivo. IL-18 markedly enhanced mature HMVEC homing to human RA ST compared with NL ST in SCID mice, confirming the role of IL-18-induced angiogenesis in RA ST in vivo.
Targeting IL-18 or its signalling intermediates may prove to be a potentially novel therapeutic strategy for angiogenesis-dependent diseases, such as RA.
白细胞介素 18（IL-18）是类风湿关节炎（RA）血管生成的一种新型介质。
研究 IL-18 在 RA 血管生成中的作用及其相关信号机制。
采用 IL-18 及其信号抑制剂，通过体内人真皮微血管内皮细胞（HMVEC）趋化、毛细血管形态发生测定和 Matrigel 塞血管生成测定，研究 IL-18 在体内的作用。利用标记有染料的 HMVEC 设计了一种新的血管生成模型，研究其归巢到 RA 和正常（NL）滑膜组织（ST）中，这些组织被移植到严重联合免疫缺陷（SCID）小鼠中。
IL-18 介导的血管生成依赖于 Src 和 Jnk，因为 Src 和 Jnk 的抑制剂阻断了 IL-18 诱导的 HMVEC 趋化、管形成和 Matrigel 塞中的血管生成。然而，Janus 激酶 2、p38、MEK、磷脂酰肌醇-3-激酶抑制剂以及血管内皮生长因子或基质衍生因子-1α的中和抗体并没有改变 IL-18 诱导的 HMVEC 迁移。这些结果通过 Jnk 或 Src 感受态或反义寡核苷酸得到了证实。此外，IL-18 诱导 HMVEC 中 Src 和 Jnk 的磷酸化。作为原理验证，IL-18 缺陷小鼠在体内 Matrigel 塞血管生成测定中的血管生成明显低于野生型小鼠。IL-18 显著增强了成熟 HMVEC 向人 RA ST 的归巢，与 NL ST 相比，在 SCID 小鼠中证实了 IL-18 诱导的血管生成在体内 RA ST 中的作用。
针对 IL-18 或其信号中间物可能成为治疗血管生成依赖性疾病（如 RA）的一种有前途的新策略。
