Cutting edge: Sanglifehrin A, a novel cyclophilin-binding immunosuppressant blocks bioactive IL-12 production by human dendritic cells

Christoph Steinschulte, Timucin Taner, Angus W. Thomson, Gregor Bein, Holger Hackstein

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Sanglifehrin A (SFA) is a novel cyclophilin-binding immunosuppressant with an unknown mechanism of action. IL-12p70 plays a critical role in the pathogenesis of inflammation and autoimmune diseases. We discovered that SFA abrogates bioactive IL-12p70 production by human dendritic cells, the major producers of this cytokine. In direct comparison to the related calcineurin inhibitor cyclosporin A and the mammalian target of rapamycin inhibitor rapamycin, SFA acts uniquely within 1 h to inhibit (80-95%) IL-12p70 production by differentiated dendritic cells. Experiments with Toll-like receptor 3 and 4 ligands show a stimulus-independent suppression. Competitive experiments with a molar excess of cyclosporin A indicate a cyclophilin A-independent blockade of IL-12p70 production. We confirm potent inhibition of IL-12p70 production by SFA using purified human blood DC. Real-time RT-PCR reveals 84-94% suppression of IL-12p40, IL-12p35, and IL-23-specific p19 transcription. These novel insights into the immunosuppressive action of SFA are likely to impact on the clinical use of this agent.

Original languageEnglish (US)
Pages (from-to)542-546
Number of pages5
JournalJournal of Immunology
Volume171
Issue number2
DOIs
StatePublished - Jul 15 2003

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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