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Pivotal Advance: Inhibition of HMGB1 nuclear translocation as a mechanism for the anti‐rheumatic effects of gold sodium thiomalate
Author(s) -
Zetterström Cecilia K.,
Jiang Weiwen,
Wähämaa Heidi,
Östberg Therese,
Aveberger AnnCharlotte,
Schierbeck Hanna,
Lotze Michael T.,
Andersson Ulf,
Pisetsky David S.,
Erlandsson Harris Helena
Publication year - 2008
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0507323
Subject(s) - biology , gold sodium thiomalate , mechanism (biology) , chromosomal translocation , pharmacology , immunology , microbiology and biotechnology , biochemistry , rheumatoid arthritis , gene , philosophy , epistemology
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‐γ, polyinosinic:polycytidylic acid, IFN‐β, 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‐β 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‐β 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.