Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Drive, Ann Arbor, MI 48109, USA.
Arthritis Res Ther. 2010;12(3):R118. doi: 10.1186/ar3055. Epub 2010 Jun 16.
The function of interleukin-18 (IL-18) was investigated in pertinent animal models of rodent rheumatoid arthritis (RA) to determine its proinflammatory and monocyte recruitment properties.
We used a modified Boyden chemotaxis system to examine monocyte recruitment to recombinant human (rhu) IL-18 in vitro. Monocyte recruitment to rhuIL-18 was then tested in vivo by using an RA synovial tissue (ST) severe combined immunodeficient (SCID) mouse chimera. We defined monocyte-specific signal-transduction pathways induced by rhuIL-18 with Western blotting analysis and linked this to in vitro monocyte chemotactic activity. Finally, the ability of IL-18 to induce a cytokine cascade during acute joint inflammatory responses was examined by inducing wild-type (Wt) and IL-18 gene-knockout mice with zymosan-induced arthritis (ZIA).
We found that intragraft injected rhuIL-18 was a robust monocyte recruitment factor to both human ST and regional (inguinal) murine lymph node (LN) tissue. IL-18 gene-knockout mice also showed pronounced reductions in joint inflammation during ZIA compared with Wt mice. Many proinflammatory cytokines were reduced in IL-18 gene-knockout mouse joint homogenates during ZIA, including macrophage inflammatory protein-3alpha (MIP-3alpha/CCL20), vascular endothelial cell growth factor (VEGF), and IL-17. Signal-transduction experiments revealed that IL-18 signals through p38 and ERK1/2 in monocytes, and that IL-18-mediated in vitro monocyte chemotaxis can be significantly inhibited by disruption of this pathway.
Our data suggest that IL-18 may be produced in acute inflammatory responses and support the notion that IL-18 may serve a hierarchic position for initiating joint inflammatory responses.
本研究旨在通过相关的啮齿类关节炎动物模型，探索白细胞介素-18（IL-18）的功能，以确定其促炎和单核细胞募集特性。
我们使用改良的 Boyden 趋化系统，在体外研究重组人（rhu）IL-18 对单核细胞的募集作用。然后，通过关节炎滑膜组织（ST）严重联合免疫缺陷（SCID）鼠嵌合体模型，在体内检测 rhuIL-18 对单核细胞的募集作用。我们通过 Western blot 分析确定了 rhuIL-18 诱导的单核细胞特异性信号转导途径，并将其与体外单核细胞趋化活性相关联。最后，通过诱导野生型（Wt）和 IL-18 基因敲除小鼠发生酵母聚糖诱导的关节炎（ZIA），研究了 IL-18 在急性关节炎症反应中诱导细胞因子级联反应的能力。
我们发现，注入移植物内的 rhuIL-18 是一种强有力的人 ST 和局部（腹股沟）鼠淋巴结（LN）组织单核细胞募集因子。与 Wt 小鼠相比，IL-18 基因敲除小鼠在 ZIA 中也表现出明显减轻的关节炎症。在 ZIA 期间，IL-18 基因敲除小鼠关节匀浆中的许多促炎细胞因子减少，包括巨噬细胞炎性蛋白-3α（MIP-3α/CCL20）、血管内皮细胞生长因子（VEGF）和 IL-17。信号转导实验表明，IL-18 通过 p38 和 ERK1/2 在单核细胞中信号转导，并且 IL-18 介导的体外单核细胞趋化作用可以通过破坏该途径而显著抑制。
我们的数据表明，IL-18 可能在急性炎症反应中产生，并支持 IL-18 可能在启动关节炎症反应中起分层作用的观点。
