IL-33 induces neutrophil migration in rheumatoid arthritis and is a target of anti-TNF therapy
IL-33 induces neutrophil migration in rheumatoid arthritis and is a target of anti-TNF therapy
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DOI：
10.1136/ard.2009.122655
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发表时间：
2010-09-01
影响因子：
27.4
通讯作者：
Cunha, Fernando Q.
中科院分区：
文献类型：
--
作者：
Verri, Waldiceu A., Jr.;Souto, Fabricio O.;Cunha, Fernando Q.
目的白细胞介素33（IL-33）是IL-1家族的新成员，通过其受体ST 2（IL-33 R）介导信号转导，在Th 2和肥大细胞应答中发挥重要作用。这项研究表明，IL-33编排中性粒细胞迁移arthritis.Methods和结果甲基化牛血清白蛋白（mBSA）的mBSA免疫小鼠的膝关节中的挑战诱导局部中性粒细胞迁移伴随着增加IL-33 R和IL-33 mRNA的表达。用可溶性IL-33 R（一种IL-33诱饵受体）全身和局部处理可抑制细胞迁移，但在IL-33 R缺陷小鼠中不明显。IL-33注射还诱导IL-33 R依赖性中性粒细胞迁移。关节中抗原和IL-33诱导的中性粒细胞迁移依赖于CXCL 1、CCL 3、肿瘤坏死因子α（TNF α）和IL-1 β的合成。滑膜组织、巨噬细胞和活化的中性粒细胞表达IL-33 R。IL-33通过激活巨噬细胞产生趋化因子和细胞因子以及通过直接作用于中性粒细胞来诱导中性粒细胞迁移。重要的是，来自用抗TNF α抗体（英夫利西单抗）成功治疗的类风湿性关节炎患者的中性粒细胞表达的IL-33 R水平显著低于单独用甲氨蝶呤治疗的患者。结论抑制中性粒细胞IL-33 R表达，阻止IL-33诱导的中性粒细胞迁移，可能是抗TNF-α治疗炎症的重要机制。
Objectives Interleukin 33 (IL-33) is a new member of the IL-1 family of cytokines which signals via its receptor, ST2 (IL-33R), and has an important role in Th2 and mast cell responses. This study shows that IL-33 orchestrates neutrophil migration in arthritis.Methods and results Methylated bovine serum albumin (mBSA) challenge in the knee joint of mBSA-immunised mice induced local neutrophil migration accompanied by increased IL-33R and IL-33 mRNA expression. Cell migration was inhibited by systemic and local treatments with soluble (s) IL-33R, an IL-33 decoy receptor, and was not evident in IL-33R-deficient mice. IL-33 injection also induced IL-33R-dependent neutrophil migration. Antigen- and IL-33-induced neutrophil migration in the joint was dependent on CXCL1, CCL3, tumour necrosis factor a (TNF alpha) and IL-1 beta synthesis. Synovial tissue, macrophages and activated neutrophils expressed IL-33R. IL-33 induces neutrophil migration by activating macrophages to produce chemokines and cytokines and by directly acting on neutrophils. Importantly, neutrophils from patients with rheumatoid arthritis successfully treated with anti-TNF alpha antibody (infliximab) expressed significantly lower levels of IL-33R than patients treated with methotrexate alone. Only neutrophils from patients treated with methotrexate alone or from normal donors stimulated with TNF alpha responded to IL-33 in chemotaxis.Conclusions These results suggest that suppression of IL-33R expression in neutrophils, preventing IL-33-induced neutrophil migration, may be an important mechanism of anti-TNF alpha therapy of inflammation.