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| Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3 |
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| Author(s): Kanneganti TD, Ozoren N, Body-Malapel M, Amer A, Park JH, Franchi L, Whitfield J, Barchet W, Colonna M, Vandenabeele P, Bertin J, Coyle A, Grant EP, Akira S, Nunez G |
| Source: NATURE Volume: 440 Issue: 7081 Pages: 233-236 Published: MAR 9 2006 |
| Times Cited: 248 References: 27 |
| Abstract: Missense mutations in the CIAS1 gene cause three autoinflammatory disorders: familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multiple-system inflammatory disease(1). Cryopyrin (also called Nalp3), the product of CIAS1, is a member of the NOD-LRR protein family that has been linked to the activation of intracellular host defence signalling pathways(2,3). Cryopyrin forms a multi-protein complex termed 'the inflammasome', which contains the apoptosis-associated speck-like protein (ASC) and caspase-1, and promotes caspase-1 activation and processing of pro-interleukin (IL)-1 beta (ref. 4). Here we show the effect of cryopyrin deficiency on inflammasome function and immune responses. Cryopyrin and ASC are essential for caspase-1 activation and IL-1 beta and IL-18 production in response to bacterial RNA and the imidazoquinoline compounds R837 and R848. In contrast, secretion of tumour-necrosis factor-alpha and IL-6, as well as activation of NF-kappa B and mitogen-activated protein kinases (MAPKs) were unaffected by cryopyrin deficiency. Furthermore, we show that Toll-like receptors and cryopyrin control the secretion of IL-1 beta and IL-18 through different intracellular pathways. These results reveal a critical role for cryopyrin in host defence through bacterial RNA-mediated activation of caspase-1, and provide insights regarding the pathogenesis of autoinflammatory syndromes. |
| Document Type: Article |
| Language: English |
| Reprint Address: Nunez, G (reprint author), Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA |
Addresses:
1. Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA
2. Ctr Comprehens Canc, Ann Arbor, MI 48109 USA
3. Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA
4. Univ Ghent, Dept Mol Biomed Res, B-9052 Zwijnaarde, Belgium
5. Millennium Pharmaceut Inc, Cambridge, MA 02139 USA
6. Osaka Univ, Microbial Dis Res Inst, Dept Host Def, Osaka 5650871, Japan |
| Publisher: NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND |
| Subject Category: Multidisciplinary Sciences |
| IDS Number: 019MC |
| ISSN: 0028-0836 |
| DOI: 10.1038/nature04517 |
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