High mobility group box chromosomal protein 1, a DNA binding cytokine, induces arthritis
High mobility group box chromosomal protein 1, a DNA binding cytokine, induces arthritis
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DOI：
10.1002/art.11028
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发表时间：
2003-06-01
影响因子：
--
通讯作者：
Tarkowski, A
中科院分区：
文献类型：
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作者：
Pullerits, R;Jonsson, IM;Tarkowski, A
Objective.目的探讨高迁移率族蛋白1（HMGB-1）在关节炎发病机制中的作用。小鼠关节内注射1 μ g或5 μ g HMGB-1。在注射后第4、7和28天解剖关节，并进行组织病理学和免疫化学评价。为了研究不同的白色血细胞群体对于关节炎发展的重要性，进行了体内细胞去除程序。另外，在HMGB-1存在的情况下培养脾细胞，通过电泳迁移率变动分析检测核因子-κ B（NF-κ B）活化。将重组HMGB-1（rHMGB-1）注射到不同的小鼠品系中，导致80%的动物出现关节炎的总体频率。炎症的特征为轻度至中度滑膜炎，并持续至少28天。在发炎的滑膜中发现的大多数细胞是Mac-1+巨噬细胞，而仅检测到少数CD 4+淋巴细胞。在某些情况下，在注射HMGB-1后7天和28天观察到血管翳形成。在单核细胞、粒细胞耗竭或缺乏T/B淋巴细胞的小鼠之间，关节炎的发生率和严重程度没有显著差异。然而，联合去除单核细胞和中性粒细胞导致关节炎发病率降低43%。白细胞介素-1（IL-1）受体缺陷的小鼠在用HMGB-1激发后未发生炎症。体外实验结果证实了这一发现，rHMGB-1激活NF-κ 3，这是导致IL-1产生的主要途径。我们的研究结果表明，HMGB-1不仅仅是炎症反应的表达，它本身通过激活巨噬细胞并通过NF-κ B激活诱导IL-1的产生来触发关节炎症。
Objective. To examine the potential role of high mobility group box chromosomal protein 1 (HMGB-1) in the pathogenesis of arthritis.Methods. Mice were injected intraarticularly with 1 mug or 5 mug of HMGB-1. Joints were dissected on days 4, 7, and 28 after injection and were evaluated histopathologically and immunohistochemically. To investigate the importance of different white blood cell populations for the development of arthritis, in vivo cell depletion procedures were performed.. In addition, spleen cells were cultured in the presence of HMGB-1, and nuclear factor kappaB (NF-kappaB) activation was detected by electrophoretic mobility shift assay.Results. Injection of recombinant HMGB-1 (rHMGB-1) into different mouse strains resulted in an overall frequency of arthritis in 80% of the animals. The inflammation was characterized by mild to moderate synovitis and lasted for at least 28 days. The majority of cells found in the inflamed synovium were Mac-1+ macrophages, whereas only a few CD4+ lymphocytes were detected. Pannus formation was observed in some cases 7 and 28 days after HMGB-1 injection. No significant differences were found with respect to incidence and severity of arthritis between mice depleted of monocytes, granulocytes, or lacking T/B lymphocytes. However, combined removal of monocytes and neutrophils resulted in a 43% lower incidence of arthritis. Mice rendered deficient in the interleukin-1 (IL-1) receptor did not develop inflammation upon challenge with HMGB-1. In vitro data corroborate this finding, showing that rHMGB-1 activated NF-kappa3, a major pathway leading to IL-1 production.Conclusion. Our results indicate that HMGB-1 is not a mere expression of inflammatory responses, but on its own, it triggers joint inflammation by activating macrophages, and inducing production of IL-1 via NF-kappaB activation.