期刊
CELL DEATH & DISEASE
卷 3, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cddis.2012.176
关键词
necroptosis; RIPK1; IDO; necrostatin; SIRS; sepsis
类别
资金
- European grant [MRTN-CT-035624, FP7-200767]
- Belgian grant [IAP 6/18, IAP 7/32]
- Flemish grants (Research Foundation Flanders) [FWO G.0875.11, FWO G.0973.11, FWO G.0A45.12N]
- Ghent University
- Flanders Institute for Biotechnology
- Flemish Government [BOF09/01M00709]
- 'Institute for the promotion of Innovation by Science and Technology in Flanders' [IWT SB63424]
- Ghent University [BOF B/09683/02]
Necrostatin-1 (Nec-1) is widely used in disease models to examine the contribution of receptor-interacting protein kinase (RIPK) 1 in cell death and inflammation. We studied three Nec-1 analogs: Nec-1, the active inhibitor of RIPK1, Nec-1 inactive (Nec-1i), its inactive variant, and Nec-1 stable (Nec-1s), its more stable variant. We report that Nec-1 is identical to methyl-thiohydantointryptophan, an inhibitor of the potent immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO). Both Nec-1 and Nec-1i inhibited human IDO, but Nec-1s did not, as predicted by molecular modeling. Therefore, Nec-1s is a more specific RIPK1 inhibitor lacking the IDO-targeting effect. Next, although Nec-1i was similar to 100 x less effective than Nec-1 in inhibiting human RIPK1 kinase activity in vitro, it was only 10 times less potent than Nec-1 and Nec-1s in a mouse necroptosis assay and became even equipotent at high concentrations. Along the same line, in vivo, high doses of Nec-1, Nec-1i and Nec-1s prevented tumor necrosis factor (TNF)-induced mortality equally well, excluding the use of Nec-1i as an inactive control. Paradoxically, low doses of Nec-1 or Nec-1i, but not Nec -1s, even sensitized mice to TNF-induced mortality. Importantly, Nec-1s did not exhibit this low dose toxicity, stressing again the preferred use of Nec-1s in vivo. Our findings have important implications for the interpretation of Nec-1-based data in experimental disease models. Cell Death and Disease (2012) 3, e437; doi:10.1038/cddis.2012.176; published online 29 November 2012
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