Pullerits Rille, Jonsson Ing-Marie, Verdrengh Margareta, Bokarewa Maria, Andersson Ulf, Erlandsson-Harris Helena, Tarkowski Andrej
Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, University of Göteborg, Gothenburg, Sweden.
Arthritis Rheum. 2003 Jun;48(6):1693-700. doi: 10.1002/art.11028.
To examine the potential role of high mobility group box chromosomal protein 1 (HMGB-1) in the pathogenesis of arthritis.
Mice were injected intraarticularly with 1 microg or 5 microg 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.
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-kappaB, a major pathway leading to IL-1 production.
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.
探讨高迁移率族蛋白B1（HMGB-1）在关节炎发病机制中的潜在作用。
向小鼠关节腔内注射1微克或5微克HMGB-1。在注射后第4天、第7天和第28天解剖关节，并进行组织病理学和免疫组织化学评估。为研究不同白细胞群体在关节炎发展中的重要性，进行了体内细胞清除程序。此外，在有HMGB-1存在的情况下培养脾细胞，并通过电泳迁移率变动分析检测核因子κB（NF-κB）的激活情况。
向不同小鼠品系注射重组HMGB-1（rHMGB-1）导致80%的动物出现关节炎。炎症的特征为轻度至中度滑膜炎，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CD4+淋巴细胞。在HMGB-1注射后7天和28天，部分病例观察到血管翳形成。在单核细胞、粒细胞耗竭或缺乏T/B淋巴细胞的小鼠之间，关节炎的发病率和严重程度未发现显著差异。然而，单核细胞和中性粒细胞联合清除导致关节炎发病率降低43%。白细胞介素-1（IL-1）受体缺陷的小鼠在受到HMGB-1攻击时未发生炎症。体外数据证实了这一发现，表明rHMGB-1激活了NF-κB，这是导致IL-1产生的主要途径。
我们的结果表明，HMGB-1不仅仅是炎症反应的一种表达，其本身可通过激活巨噬细胞并经由NF-κB激活诱导IL-1产生来引发关节炎症。
