西亚试剂：Pivotal Advance: Inhibition of HMGB1 nuclear translocation

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: 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/orSupernatant 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

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