Author
Listed:
- Ueli Nachbur
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
- Che A. Stafford
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
- Aleksandra Bankovacki
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
- Yifan Zhan
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
- Lisa M. Lindqvist
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
- Berthe K. Fiil
(Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Ludwig Institute for Cancer Research, University of Oxford)
- Yelena Khakham
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
- Hyun-Ja Ko
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
- Jarrod J. Sandow
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
- Hendrik Falk
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne
Cancer Therapeutics CRC)
- Jessica K. Holien
(ACRF Rational Drug Discovery Centre, St Vincent’s Institute of Medical Research)
- Diep Chau
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
- Joanne Hildebrand
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
- James E. Vince
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
- Phillip P. Sharp
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
- Andrew I. Webb
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
- Katherine A. Jackman
(The Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, Austin Campus)
- Sabrina Mühlen
(University of Melbourne)
- Catherine L. Kennedy
(University of Melbourne)
- Kym N. Lowes
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
- James M. Murphy
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
- Mads Gyrd-Hansen
(Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Ludwig Institute for Cancer Research, University of Oxford)
- Michael W. Parker
(ACRF Rational Drug Discovery Centre, St Vincent’s Institute of Medical Research
Bio21 Molecular Science and Biotechnology Institute, University of Melbourne)
- Elizabeth L. Hartland
(University of Melbourne)
- Andrew M. Lew
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
- David C. S. Huang
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
- Guillaume Lessene
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
- John Silke
(The Walter and Eliza Hall Institute of Medical Research
University of Melbourne)
Abstract
Intracellular nucleotide binding and oligomerization domain (NOD) receptors recognize antigens including bacterial peptidoglycans and initiate immune responses by triggering the production of pro-inflammatory cytokines through activating NF-κB and MAP kinases. Receptor interacting protein kinase 2 (RIPK2) is critical for NOD-mediated NF-κB activation and cytokine production. Here we develop and characterize a selective RIPK2 kinase inhibitor, WEHI-345, which delays RIPK2 ubiquitylation and NF-κB activation downstream of NOD engagement. Despite only delaying NF-κB activation on NOD stimulation, WEHI-345 prevents cytokine production in vitro and in vivo and ameliorates experimental autoimmune encephalomyelitis in mice. Our study highlights the importance of the kinase activity of RIPK2 for proper immune responses and demonstrates the therapeutic potential of inhibiting RIPK2 in NOD-driven inflammatory diseases.
Suggested Citation
Ueli Nachbur & Che A. Stafford & Aleksandra Bankovacki & Yifan Zhan & Lisa M. Lindqvist & Berthe K. Fiil & Yelena Khakham & Hyun-Ja Ko & Jarrod J. Sandow & Hendrik Falk & Jessica K. Holien & Diep Chau, 2015.
"A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production,"
Nature Communications, Nature, vol. 6(1), pages 1-13, May.
Handle:
RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7442
DOI: 10.1038/ncomms7442
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