Duke大學醫(yī)學中心的科學家最近揭開了金子治療功效的秘密——這能使金鹽用于風濕性關(guān)節(jié)炎和其它炎癥疾病的治療。
早在1900年代早期醫(yī)師就通過注射金鹽來減輕關(guān)節(jié)炎的疼痛,。但這種治療的代價也是高昂的：注射通常需要數(shù)月才發(fā)揮作用，副作用也很嚴重,，包括皮疹、口瘡,、腎臟損傷,，有時甚至會發(fā)生骨髓造血功能障礙。最近新的治療手段例如甲氨蝶呤和其它生物工程藥物已經(jīng)替代了金,，金鹽只有在其它藥物無效時才使用,。
Duke風濕病學和免疫學系主任David Pisetsky說：“我們不能忽視金鹽的作用，科學家并不清楚金的作用機制?，F(xiàn)在我們?nèi)〉昧诵掳l(fā)現(xiàn)，并能使用這些機制制造新的治療關(guān)節(jié)炎的藥物,。”Pisetsky長期以來對一種激發(fā)炎癥的分子——HMBG1感興趣,，它對風濕性關(guān)節(jié)炎的發(fā)生很關(guān)鍵。HMBG1能通過進入細胞核或釋放出細胞起作用,。
在細胞核內(nèi),，HMGB1是基因信息從DNA向RNA轉(zhuǎn)錄的關(guān)鍵分子。但當HMGB1釋放出細胞時它將激發(fā)免疫系統(tǒng)產(chǎn)生炎癥反應,。Pisetsky說：“有趣的是HMGB1在體內(nèi)各處產(chǎn)生并不均衡,。它們在關(guān)節(jié)周圍的滑液組織中濃度非常高。”
Pisetsky和Pittsburgh大學,、瑞典Karolinska研究院合作,，刺激老鼠和人免疫系統(tǒng)細胞分泌HMGB1，然后用金鹽治療,。結(jié)果發(fā)現(xiàn)金鹽能抑制細胞核釋放HMGB1,，這能減輕炎癥反應。Pisetsky說：“對于關(guān)節(jié)炎患者而言，將HMGB1控制在細胞核內(nèi)是有利的,。”金能通過作用于兩種幫助細胞釋放HMBG1的分子抑制其釋放,，這兩種分子是β干擾素和一氧化氮。
結(jié)果將發(fā)表在2008年1月的《白血球生物學雜志》（Journal of Leukocyte Biology）上,，目前已經(jīng)刊登于網(wǎng)絡版,。Pisetsky表示：“我們已經(jīng)確定了至少一種金幫助關(guān)節(jié)炎治療的機制，或許能用其發(fā)明新的安全療法,。”目前科學家還需要進行更多實驗以確定以上機制在動物和人體都有效,。（ 教育部科技發(fā)展中心）
原文鏈接：http://www.physorg.com/news112286811.html
原始出處:
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: [email protected] .
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
