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Thalidomide Inhibits Activation of Caspase-1¹

Institute of Cell Biology, Department of Biology, Swiss Federal Institute of Technology Zurich, Switzerland

Thalidomide is an efficient anti-inflammatory and anti-angiogenic drug, but its therapeutic use is problematic due to a strong teratogenic activity. Nevertheless, thalidomide was approved for the treatment of inflammatory skin diseases and certain types of cancer, and it is extensively tested for several other indications. Recently, we demonstrated that active caspase-1, whose activation is dependent on inflammasome complexes, is required for unconventional protein secretion of proinflammatory cytokines such as IL-1 and of the proangiogenic fibroblast growth factor 2. In this study, we show that pharmacological doses of thalidomide strongly reduced the secretion of both proteins. Thalidomide-treated cells also released less of other leaderless proteins, which require caspase-1 activity for their secretion. In line with these findings, the drug inhibited activation and activity of caspase-1 in cultured cells but not in vitro. The latter finding suggests that the pharmacological activity is exerted by a metabolite of the drug. The anti-inflammatory activity of thalidomide was also mediated via caspase-1 in mice. These findings represent a novel mechanism by which thalidomide exerts its pharmacological activity and suggest that inhibition of the activity of IL-1 might represent a novel strategy to substitute thalidomide.

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 This work was supported by the Swiss National Science Foundation (Grant 3100A0-104170 to H.D.B.) and by the Swiss Federal Institute of Technology Zurich.

² Address correspondence and reprint requests to Hans-Dietmar Beer, ETH Zurich, Institute of Cell Biology, HPM D44, Schafmattstrasse 18, CH-8093 Zurich, Switzerland. E-mail address: dietmar.beer{at}cell.biol.ethz.ch

³ Abbreviations used in this paper: MSU, monosodium urate; CARD, caspase recruitment domain; FGF, fibroblast growth factor; WT, wild type; LDH, lactate dehydrogenase; Asc, apoptosis-associated speck-like protein containing a CARD; IL-1Ra, IL-1 receptor antagonist; NALP, Nacht, LRR, and Pyrin domain-containing protein; YVAD, Ac-Tyr-Val-Ala-Asp-chloromethylketone.