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J. Biol. Chem., Vol. 282, Issue 4, 2250-2258, January 26, 2007

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The Anti-rheumatic Gold Salt Aurothiomalate Suppresses Interleukin-1-induced Hyaluronan Accumulation by Blocking HAS1 Transcription and by Acting as a COX-2 Transcriptional Repressor^*

From the Ludwig Boltzmann Institute for Rheumatology and Balneology, Kurbadstrasse 10, 1100 Vienna, Austria

Gold compounds are among the oldest disease-modifying drugs and are still widely used today for treating rheumatoid arthritis. Despite decades of use, little is known about the mode of action of this class of drugs. Here we have demonstrated that aurothiomalate (AuTM) suppresses hyaluronan accumulation by blocking interleukin (IL)-1-induced hyaluronan synthase-1 transcription. We have further demonstrated that, in fibroblast-like synoviocytes (FLSs), AuTM acts as a specific COX-2 transcriptional repressor in that IL-1-induced COX-2 transcription is blocked, whereas COX-1 transcription and translation is unaffected. As a consequence, PGE2 levels released by FLS are dose-dependently reduced in cells exposed to AuTM. Of similar importance is the demonstration that AuTM does block NFB-DNA interaction. In addition, two other transcription factors implicated in inflammatory events, namely AP-1 and STAT3, are blocked as well. The effect on NFB likely explains the inhibition of COX-2 as well as that of HAS1, as both are genes that depend on the activation of NFB. Interestingly, AuTM does not interfere with IL-1-induced IB degradation, in most cases a prerequisite for subsequent NFB activation. Furthermore, evidence is presented that, in FLS, AuTM blocks NFB-DNA interaction neither by binding to NFB binding sites nor by interacting with activated NFB proteins. Taken together, AuTM treatment of FLS blocks two of the most important proinflammatory events that are associated with rheumatoid arthritis. AuTM blocks the release of PGE2 and prevents the activation of NFB, therefore blocking IL-1-induced hyaluronan accumulation and likely a series of other pro-inflammatory NFB-dependent genes.

Received for publication, May 24, 2006 , and in revised form, October 10, 2006.

^* This work was supported in part by grants from the Austrian National Bank, the Austrian Ministry of Health and Women, and the Austrian Ministry of Education, Science, and Culture. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Ludwig Boltzmann Institute for Rheumatology and Balneology, Kurbadstrasse 10, 1100 Vienna, Austria. Tel.: 43-1-680099231; Fax: 43-1-680099234; E-mail: karlms{at}excite.com.

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