Journal article
A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production
U Nachbur, CA Stafford, A Bankovacki, Y Zhan, LM Lindqvist, BK Fiil, Y Khakham, HJ Ko, JJ Sandow, H Falk, JK Holien, D Chau, J Hildebrand, JE Vince, PP Sharp, AI Webb, KA Jackman, S Mühlen, CL Kennedy, KN Lowes Show all
Nature Communications | Published : 2015
DOI: 10.1038/ncomms7442
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 ..
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Awarded by Juvenile Diabetes Research Foundation International
Funding Acknowledgements
We thank Professor R. Flavell for the gift of Ripk2<SUP>-/-</SUP> mice, Professor C. Day for the gift of GST-BIR2 constructs, M. Rashidi for THP-1 NF-kappa B GFP reporter cells and K. Trueman, K. Vella and R. Poppelton for assistance with animal work. The work was supported by the NHMRC (grants 1046986, 461221, 1016701, 1037321, 1043414, 1024839, 1051210, 606788, a CJ Martin fellowship to K.A.J. and J.H., a Peter Doherty Early Career Fellowship (1035502) to L.M.L. and research fellowships to J.S., J.V., M.W.P., A.M.L. and D.C.S.H.), the ARC (fellowships to U.N. (FT130100166), C.L.K. (DE12010340) and J.M.M. (FT 100100100)), the WEHI de Burgh Fellowship to G.L., the Rebecca Cooper Foundation, the Juvenile Diabetes Research Foundation, the Leukaemia and Lymphoma Society, the Australian Cancer Research Foundation, Catalyst Therapeutics, the Novo Nordisk Foundation (MGH, BKF) and the Lundbeck Foundation (MGH). U.N. was also supported by the Swiss National Science Foundation (SNSF, fellowship #PA00P3_126249). M.G.-H. was supported by a Steno Fellowship from the Danish Council for Independent Research-Natural Sciences. J.K.H. is supported by a joint Cure Cancer/Leukemia Foundation Fellowship. L.M.L. is a Bisby Fellow and thanks the CIHR for a Post-PhD Fellowship. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS (#361646).