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 Citations (Scopus)

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
Externally publishedYes

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Cyclophilins
Interleukin-12
Immunosuppressive Agents
Dendritic Cells
Sirolimus
Cyclosporine
Interleukin-23 Subunit p19
Interleukin-12 Subunit p35
Cyclophilin A
Toll-Like Receptor 3
Interleukin-12 Subunit p40
Toll-Like Receptor 4
Autoimmune Diseases
Real-Time Polymerase Chain Reaction
sanglifehrin A
Cytokines
Ligands
Inflammation

ASJC Scopus subject areas

  • Immunology

Cite this

Cutting edge : Sanglifehrin A, a novel cyclophilin-binding immunosuppressant blocks bioactive IL-12 production by human dendritic cells. / Steinschulte, Christoph; Taner, Timucin; Thomson, Angus W.; Bein, Gregor; Hackstein, Holger.

In: Journal of Immunology, Vol. 171, No. 2, 15.07.2003, p. 542-546.

Research output: Contribution to journalArticle

Steinschulte, Christoph ; Taner, Timucin ; Thomson, Angus W. ; Bein, Gregor ; Hackstein, Holger. / Cutting edge : Sanglifehrin A, a novel cyclophilin-binding immunosuppressant blocks bioactive IL-12 production by human dendritic cells. In: Journal of Immunology. 2003 ; Vol. 171, No. 2. pp. 542-546.
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