TY - JOUR
T1 - Cutting edge
T2 - Sanglifehrin A, a novel cyclophilin-binding immunosuppressant blocks bioactive IL-12 production by human dendritic cells
AU - Steinschulte, Christoph
AU - Taner, Timucin
AU - Thomson, Angus W.
AU - Bein, Gregor
AU - Hackstein, Holger
PY - 2003/7/15
Y1 - 2003/7/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.171.2.542
DO - 10.4049/jimmunol.171.2.542
M3 - Article
C2 - 12847216
AN - SCOPUS:0038446860
SN - 0022-1767
VL - 171
SP - 542
EP - 546
JO - Journal of Immunology
JF - Journal of Immunology
IS - 2
ER -