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This article is part of the supplement: 7th European Workshop on Immune-Mediated Inflammatory Diseases

Open Access Poster presentation

Inhibition of cystathionine-γ-lyase controls interleukin-12 production by dendritic cells, delayed-type hypersensitivity and transplant rejection

Romain Vuillefroy de Silly12, Flora Coulon12, Nicolas Poirier12, Vojislav Jovanovic1, Sophie Brouard1, Véronique Ferchaud-Roucher23, Gilles Blancho12 and Bernard Vanhove12*

  • * Corresponding author: Bernard Vanhove

Author Affiliations

1 INSERM, UMR 1064, ITUN, Nantes, France

2 University of Nantes, Nantes University Hospital Center, Nantes, France

3 INSERM, UMR915, Nantes, France

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Journal of Translational Medicine 2012, 10(Suppl 3):P62  doi:10.1186/1479-5876-10-S3-P62

The electronic version of this article is the complete one and can be found online at: http://www.translational-medicine.com/content/10/S3/P62


Published:28 November 2012

© 2012 Vuillefroy de Silly et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background

γ-cystathionase (CSE) is a rate-limiting enzyme of the trans-sulfuration pathway which converts methionine and cystathionine into cysteine and H2S. T cells are deficient in CSE and cysteine import and therefore are metabolically dependent on accessory cells for cysteine supply.

Methods and results

In the current study, we demonstrated that pharmacological blockade of CSE with the irreversible inhibitor propargylglycine (PPG) delayed heart allograft rejection (median survival of 26.5 days instead of 9 in controls) and abrogated type IV hypersensitivity to keyhole limpet haemocyanin (Th-1 response), but did not modify antibody responses (Th-2 response). The dominant biological effect of CSE blockade was a repression of the IL-12 p40, T-Bet and IL-1β transcripts inside the graft paralleled with a decrease, at the protein level, of IL-12 and IFN-γ. In parallel, we found that tolerance induced by costimulation blockade or immunosuppression after heart and kidney allotransplantation in the LEW.1W to LEW.1A rat model was associated with a two to five fold repression of intragraft CSE, as well as of several other enzymes of the trans-sulfuration pathway. Monocytes and Dendritic cells treated by PPG or by the reversible CSE inhibitor, β-cyano alanine, as well as by siRNA specific for CSE, dose-dependently and differentially regulated production of IL-12 cytokine. The effect was independent of NFkB or H2S production, but could be assigned to a modulation of intracellular cysteine content.

Conclusion

Our results identify CSE as a novel factor that plays a critical role in IL-12 production by monocytes and DCs by modulating intracellular cysteine levels, which in turn controls Th-1 type immune responses.