Thalidomide inhibits activation of caspase-1

Martin Keller, Gabriel Sollberger, Hans Dietmar Beer

Research output: Contribution to journalArticlepeer-review

53 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)5593-5599
Number of pages7
JournalJournal of Immunology
Volume183
Issue number9
Early online date20 Oct 2009
DOIs
Publication statusPublished - 1 Nov 2009

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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