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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.

Original publication

DOI

10.1038/ncomms7442

Type

Journal article

Journal

Nature communications

Publication Date

17/03/2015

Volume

6

Pages

6442 - 6442

Addresses

1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3010, Australia.

Keywords

Immune System, Animals, Mice, Inbred C57BL, Mice, Inbred NOD, Humans, Mice, Encephalomyelitis, Autoimmune, Experimental, Inflammation, NF-kappa B, Recombinant Proteins, Ubiquitin, Adenosine Triphosphate, Cytokines, Chromatography, Liquid, Inhibitory Concentration 50, Signal Transduction, MAP Kinase Signaling System, Protein Conformation, Protein Binding, Female, Male, Receptor-Interacting Protein Serine-Threonine Kinases, Receptor-Interacting Protein Serine-Threonine Kinase 2, Tandem Mass Spectrometry, Interferon-gamma