Cutting edge: Necrosis activates the NLRP3 inflammasome.

Abstract

Cells undergoing necrosis release endogenous danger signals that possess proinflammatory potential. In this study we show that mature IL-1beta and IL-18 are released by necrotic cells but not by apoptotic cells. We identify 7-bromoindirubin-3'-oxime, an indirubin oxime derivative that induces necrosis, as a potent inducer of caspase-1 activation and release of mature IL-1beta and IL-18. Inflammasome activation was triggered by other necrosis-inducing treatments but was not observed in response to apoptosis-inducing stimuli. Necrosis-induced inflammasome activation was mediated by the NLRP3 and ASC molecules. Release of IL-18 and IL-1beta in response to necrosis-inducing stimuli was observed in THP-1 macrophages and the MSTO-211H human mesothelioma cell line independently of LPS priming. Using the in vivo model of naphthalene-induced airway epithelial cell injury, we showed that necrosis activates the ASC inflammasome in vivo. Our study identifies a new mechanism through which necrosis generates proinflammatory molecules that contributes to the sterile inflammatory response.

• Authors: Hanfen Li, Aditya Ambade, Fabio Re
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 183 Issue 3 Pg. 1528-32 (Aug 01 2009) ISSN: 1550-6606 [Electronic] United States
• PMID: 19596994 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 7-bromoindirubin-3'-oxime
• Carrier Proteins
• Indoles
• Interleukin-18
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Oximes

Topics

• Animals
• Carrier Proteins (metabolism)
• Cell Line
• Epithelial Cells (pathology)
• Humans
• Indoles
• Inflammation (etiology, pathology)
• Interleukin-18
• Interleukin-1beta
• Macrophages (pathology)
• Mesothelioma (pathology)
• Mice
• Mice, Knockout
• NLR Family, Pyrin Domain-Containing 3 Protein
• Necrosis (pathology)
• Oximes
• Respiratory System (pathology)