Duke大学医学中心的科学家最近揭开了金子治疗功效的秘密——这能使金盐用于风湿性关节炎和其它炎症疾病的治疗。
早在1900年代早期医师就通过注射金盐来减轻关节炎的疼痛。但这种治疗的代价也是高昂的：注射通常需要数月才发挥作用，副作用也很严重，包括皮疹、口疮、肾脏损伤，有时甚至会发生骨髓造血功能障碍。最近新的治疗手段例如甲氨蝶呤和其它生物工程药物已经替代了金，金盐只有在其它药物无效时才使用。
Duke风湿病学和免疫学系主任David Pisetsky说：“我们不能忽视金盐的作用，科学家并不清楚金的作用机制。现在我们取得了新发现，并能使用这些机制制造新的治疗关节炎的药物。”Pisetsky长期以来对一种激发炎症的分子——HMBG1感兴趣，它对风湿性关节炎的发生很关键。HMBG1能通过进入细胞核或释放出细胞起作用。
在细胞核内，HMGB1是基因信息从DNA向RNA转录的关键分子。但当HMGB1释放出细胞时它将激发免疫系统产生炎症反应。Pisetsky说：“有趣的是HMGB1在体内各处产生并不均衡。它们在关节周围的滑液组织中浓度非常高。”
Pisetsky和Pittsburgh大学、瑞典Karolinska研究院合作，刺激老鼠和人免疫系统细胞分泌HMGB1，然后用金盐治疗。结果发现金盐能抑制细胞核释放HMGB1，这能减轻炎症反应。Pisetsky说：“对于关节炎患者而言，将HMGB1控制在细胞核内是有利的。”金能通过作用于两种帮助细胞释放HMBG1的分子抑制其释放，这两种分子是β干扰素和一氧化氮。
结果将发表在2008年1月的《白血球生物学杂志》（Journal of Leukocyte Biology）上，目前已经刊登于网络版。Pisetsky表示：“我们已经确定了至少一种金帮助关节炎治疗的机制，或许能用其发明新的安全疗法。”目前科学家还需要进行更多实验以确定以上机制在动物和人体都有效。（ 教育部科技发展中心）
原文链接：http://www.physorg.com/news112286811.html
原始出处:
Published online before print October 3, 2007
Received for publication May 24, 2007.
Revised September 7, 2007.
Accepted for publication September 8, 2007.
Pivotal Advance: Inhibition of HMGB1 nuclear translocation as a mechanism for the anti-rheumatic effects of gold sodium thiomalate
Cecilia K. Zetterström *, Weiwen Jiang , Heidi Wähämaa *, Therese Östberg *, Ann-Charlotte Aveberger *, Hanna Schierbeck *, Michael T. Lotze , Ulf Andersson *@, David S. Pisetsky , and Helena Erlandsson Harris
Departments of *Woman and Child Health, Pediatric Rheumatology Research Unit, and Medicine, Rheumatology Unit, Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden; Division of Rheumatology and Immunology, Department of Medicine, Duke University, Durham, North Carolina, USA; and Surgery and Bioengineering, DAMP Laboratory, University of Pittsburg, Pittsburg, Pennsylvania, USA
@ To whom correspondence should be addressed. E-mail: Ulf.Andersson@ki.se .
Gold compounds such as gold sodium thiomalate (GST) can reduce the symptoms of rheumatoid arthritis (RA), although their mechanism of action is not well defined. As the proinflammatory mediator high mobility group box chromosomal protein 1 (HMGB1) may play a role in the pathogenesis of RA, we have performed in vitro studies to investigate whether GST inhibits HMGB1 release as the basis of its mode of action. Murine RAW 264.7 or human THP-1 macrophage cells were stimulated in culture with agents causing extracellular HMGB1 release, including LPS, IFN-, polyinosinic:polycytidylic acid, IFN-, or NO in the presence of GST, ranging from 0 µM to 250 µM. Secretion and intracellular location of HMGB1 were assessed by Western blotting, HMGB1-specific ELISPOT assay, and immunofluorescent staining. In parallel, TNF and IFN- levels were analyzed by ELISPOT and/or ELISA. Supernatant NO production was analyzed by the Griess method. At pharmacologically relevant doses, GST inhibited the extracellular release of HMGB1 from activated macrophages and caused the nuclear retention of this protein; in contrast, no effects were observed on the secretion or production of TNF. Release of the key endogenous mediators of HMGB1 translocation, IFN- and NO, was inhibited by GST. This inhibition required gold, as sodium thiomalate did not affect the responses measured. Furthermore, gold chloride also inhibited release of HMGB1. Together, these results suggest a new mechanism for the anti-rheumatic effects of gold salts in RA and the potential of drugs, which interfere with intracellular HMGB1 transport mechanisms, as novel agents to treat RA.
Key Words: gold salts • arthritis • inflammation • therapy • cytokines • immunomodulation • TNF • IFN- • nitric oxide
