title: Pivotal advance: inhibition of HMGB1 nuclear translocation as a mechanism for the anti-rheumatic effects of gold sodium thiomalate.
abstract: 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-gamma, polyinosinic:polycytidylic acid, IFN-beta, or NO in the presence of GST, ranging from 0 microM to 250 microM. Secretion and intracellular location of HMGB1 were assessed by Western blotting, HMGB1-specific ELISPOT assay, and immunofluorescent staining. In parallel, TNF and IFN-beta 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-beta 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.
authors.affiliation: Department of Woman and Child Health, Pediatric Rheumatology Research Unit, Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Cecilia K
authors.initials: CK
authors.lastname: Zetterström
authors.forename: Weiwen
authors.initials: W
authors.lastname: Jiang
authors.forename: Heidi
authors.initials: H
authors.lastname: Wähämaa
authors.forename: Therese
authors.initials: T
authors.lastname: Ostberg
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Aveberger
authors.forename: Hanna
authors.initials: H
authors.lastname: Schierbeck
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.forename: Ulf
authors.initials: U
authors.lastname: Andersson
authors.forename: David S
authors.initials: DS
authors.lastname: Pisetsky
authors.forename: Helena
authors.initials: H
authors.lastname: Erlandsson Harris
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000276:immunology; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006052:Gold Sodium Thiomalate / Q000494:pharmacology* / Q000627:therapeutic use; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D016899:Interferon-beta / Q000187:drug effects / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D006052:Gold Sodium Thiomalate; D009569:Nitric Oxide; D016899:Interferon-beta; D007371:Interferon-gamma