Reciprocal cross-talk between RANKL and interferon-γ-inducible protein 10 is responsible for bone-erosive experimental arthritis
Reciprocal cross-talk between RANKL and interferon-γ-inducible protein 10 is responsible for bone-erosive experimental arthritis
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DOI：
10.1002/art.23372
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发表时间：
2008-05-01
影响因子：
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通讯作者：
Lee, Zang Hee
中科院分区：
文献类型：
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作者：
Kwak, Han Bok;Ha, Hyunil;Lee, Zang Hee
目标。干扰素- γ诱导蛋白10 （IP-10，也称为CXCL10）是一种在T细胞迁移和增殖中起重要作用的趋化因子，可在多种细胞类型中诱导。然而，IP-10在类风湿关节炎（RA）中的作用在很大程度上仍然未知。本研究的目的是通过检查小鼠胶原诱导关节炎（CIA）模型来研究IP-10在骨吸收和RA中的潜在作用。通过迁移实验研究了IP-10对小鼠破骨细胞分化过程中T细胞的影响。采用组织学和免疫染色法测定小鼠CIA模型中IP-10的骨侵蚀活性。采用夹心酶联免疫吸附法测定血清和培养基中细胞因子水平。CIA小鼠血清IP-10浓度显著高于对照组小鼠。RANKL在破骨细胞前体中显著诱导IP-10的表达，而在成熟破骨细胞中无显著诱导作用。IP-10刺激CD4+ T细胞中RANKL和肿瘤坏死因子a （TNF - α）的表达，诱导CD4+ T细胞和破骨细胞前体共培养的破骨细胞生成。然而，IP-10在CD8+ T细胞中不诱导RANKL或TNFa。IP-10中和抗体可显著抑制CIA小鼠滑膜内CD4+ T细胞和F4/80+巨噬细胞的浸润，减轻骨破坏。此外，IP-10抗体抑制RANKL和TNFa水平。IP-10逆转录病毒感染小鼠可引起骨侵蚀。我们的研究结果表明，IP-10在CD4+ T细胞和F4/80+巨噬细胞浸润炎症关节并导致骨破坏中起关键作用。我们的结果提供了第一个证据，证明IP-10有助于炎症细胞的募集，并参与炎症关节的骨侵蚀。
Objective. Interferon-gamma-inducible protein 10 (IP-10; also called CXCL10), a chemokine important in the migration and proliferation of T cells, is induced in a wide variety of cell types. However, the role of IP-10 in rheumatoid arthritis (RA) remains largely unknown. The purpose of this study was to examine the potential role of IP-10 in bone resorption and RA through examination of a mouse model of collagen-induced arthritis (CIA).Methods. The effects of IP-10 on mouse T cells during osteoclast differentiation were examined in migration assays. The bone-erosive activity of IP-10 was determined in vivo in a mouse model of CIA by histologic and immunostaining analyses. Cytokine levels in serum and culture medium were measured with sandwich enzyme-linked immunosorbent assays.Results. Serum concentrations of IP-10 were significantly higher in mice with CIA than in control mice. RANKL greatly induced IP-10 expression in osteoclast precursors, but not in mature osteoclasts. IP-10 stimulated the expression of RANKL and tumor necrosis factor a (TNF alpha) in CD4+ T cells and induced osteoclastogenesis in cocultures of CD4+ T cells and osteoclast precursors. However, IP-10 did not induce RANKL or TNFa in CD8+ T cells. Treatment with neutralizing antibody to IP-10 significantly inhibited the infiltration of CD4+ T cells and F4/80+ macrophages into the synovium and attenuated bone destruction in mice with CIA. Furthermore, levels of RANKL and TNFa were inhibited by antibody to IP-10. Bone erosion was observed in mice infected with an IP-10 retrovirus.Conclusion. Our findings suggest that IP-10 plays a critical role in the infiltration of CD4+ T cells and F4/80+ macrophages into inflamed joints and causes bone destruction. Our results provide the first evidence that IP-10 contributes to the recruitment of inflammatory cells and is involved in bone erosion in inflamed joints.