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000138812 0247_ $$2doi$$a10.4049/jimmunol.1600035
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000138812 0247_ $$2ISSN$$a0022-1767
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000138812 0247_ $$2ISSN$$a1048-3233
000138812 0247_ $$2ISSN$$a1550-6606
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000138812 041__ $$aEnglish
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000138812 1001_ $$aPrimiano, Michael J$$b0
000138812 245__ $$aEfficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation.
000138812 260__ $$aBethesda, Md.$$bSoc.$$c2016
000138812 264_1 $$2Crossref$$3online$$bThe American Association of Immunologists$$c2016-08-12
000138812 264_1 $$2Crossref$$3print$$bThe American Association of Immunologists$$c2016-09-15
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000138812 520__ $$aA critical component of innate immune response to infection and tissue damage is the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome, and this pathway and its activation products have been implicated in the pathophysiology of a variety of diseases. NLRP3 inflammasome activation leads to the cleavage of pro-IL-1β and pro-IL-18, as well as the subsequent release of biologically active IL-1β, IL-18, and other soluble mediators of inflammation. In this study, we further define the pharmacology of the previously reported NLRP3 inflammasome-selective, IL-1β processing inhibitor CP-456,773 (also known as MCC950), and we demonstrate its efficacy in two in vivo models of inflammation. Specifically, we show that in human and mouse innate immune cells CP-456,773 is an inhibitor of the cellular release of IL-1β, IL-1α, and IL-18, that CP-456,773 prevents inflammasome activation induced by disease-relevant soluble and crystalline NLRP3 stimuli, and that CP-456,773 inhibits R848- and imiquimod-induced IL-1β release. In mice, CP-456,773 demonstrates potent inhibition of the release of proinflammatory cytokines following acute i.p. challenge with LPS plus ATP in a manner that is proportional to the free/unbound concentrations of the drug, thereby establishing an in vivo pharmacokinetic/pharmacodynamic model for CP-456,773. Furthermore, CP-456,773 reduces ear swelling in an imiquimod cream-induced mouse model of skin inflammation, and it reduces airway inflammation in mice following acute challenge with house dust mite extract. These data implicate the NLRP3 inflammasome in the pathogenesis of dermal and airway inflammation, and they highlight the utility of CP-456,773 for interrogating the contribution of the NLRP3 inflammasome and its outputs in preclinical models of inflammation and disease.
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000138812 650_7 $$2NLM Chemicals$$aCytokines
000138812 650_7 $$2NLM Chemicals$$aHeterocyclic Compounds, 4 or More Rings
000138812 650_7 $$2NLM Chemicals$$aInflammasomes
000138812 650_7 $$2NLM Chemicals$$aInterleukin-18
000138812 650_7 $$2NLM Chemicals$$aInterleukin-1alpha
000138812 650_7 $$2NLM Chemicals$$aInterleukin-1beta
000138812 650_7 $$2NLM Chemicals$$aMCC-950
000138812 650_7 $$2NLM Chemicals$$aNLR Family, Pyrin Domain-Containing 3 Protein
000138812 650_7 $$2NLM Chemicals$$aSulfones
000138812 650_2 $$2MeSH$$aFurans
000138812 650_2 $$2MeSH$$aAnimals
000138812 650_2 $$2MeSH$$aCytokines: antagonists & inhibitors
000138812 650_2 $$2MeSH$$aCytokines: immunology
000138812 650_2 $$2MeSH$$aDermatitis: drug therapy
000138812 650_2 $$2MeSH$$aDermatitis: immunology
000138812 650_2 $$2MeSH$$aDermatitis: physiopathology
000138812 650_2 $$2MeSH$$aDisease Models, Animal
000138812 650_2 $$2MeSH$$aHeterocyclic Compounds, 4 or More Rings: administration & dosage
000138812 650_2 $$2MeSH$$aHeterocyclic Compounds, 4 or More Rings: pharmacology
000138812 650_2 $$2MeSH$$aHeterocyclic Compounds, 4 or More Rings: therapeutic use
000138812 650_2 $$2MeSH$$aHumans
000138812 650_2 $$2MeSH$$aImmunity, Innate: drug effects
000138812 650_2 $$2MeSH$$aInflammasomes: antagonists & inhibitors
000138812 650_2 $$2MeSH$$aInflammation: drug therapy
000138812 650_2 $$2MeSH$$aInflammation: immunology
000138812 650_2 $$2MeSH$$aInflammation: physiopathology
000138812 650_2 $$2MeSH$$aInterleukin-18: antagonists & inhibitors
000138812 650_2 $$2MeSH$$aInterleukin-18: metabolism
000138812 650_2 $$2MeSH$$aInterleukin-1alpha: antagonists & inhibitors
000138812 650_2 $$2MeSH$$aInterleukin-1alpha: metabolism
000138812 650_2 $$2MeSH$$aInterleukin-1beta: antagonists & inhibitors
000138812 650_2 $$2MeSH$$aInterleukin-1beta: immunology
000138812 650_2 $$2MeSH$$aMice
000138812 650_2 $$2MeSH$$aNLR Family, Pyrin Domain-Containing 3 Protein: antagonists & inhibitors
000138812 650_2 $$2MeSH$$aPneumonia: drug therapy
000138812 650_2 $$2MeSH$$aPneumonia: immunology
000138812 650_2 $$2MeSH$$aPneumonia: physiopathology
000138812 650_2 $$2MeSH$$aSignal Transduction
000138812 650_2 $$2MeSH$$aSulfones: administration & dosage
000138812 650_2 $$2MeSH$$aSulfones: pharmacology
000138812 650_2 $$2MeSH$$aSulfones: therapeutic use
000138812 650_2 $$2MeSH$$aIndenes
000138812 650_2 $$2MeSH$$aSulfonamides
000138812 7001_ $$aLefker, Bruce A$$b1
000138812 7001_ $$aBowman, Michael R$$b2
000138812 7001_ $$aBree, Andrea G$$b3
000138812 7001_ $$aHubeau, Cedric$$b4
000138812 7001_ $$aBonin, Paul D$$b5
000138812 7001_ $$0P:(DE-2719)2810930$$aMangan, Matthew$$b6$$udzne
000138812 7001_ $$aDower, Ken$$b7
000138812 7001_ $$aMonks, Brian G$$b8
000138812 7001_ $$aCushing, Leah$$b9
000138812 7001_ $$aWang, Stephen$$b10
000138812 7001_ $$aGuzova, Julia$$b11
000138812 7001_ $$aJiao, Aiping$$b12
000138812 7001_ $$aLin, Lih-Ling$$b13
000138812 7001_ $$0P:(DE-2719)2000062$$aLatz, Eicke$$b14$$udzne
000138812 7001_ $$aHepworth, David$$b15
000138812 7001_ $$0P:(DE-HGF)0$$aHall, J Perry$$b16$$eCorresponding author
000138812 77318 $$2Crossref$$3journal-article$$a10.4049/jimmunol.1600035$$b : The American Association of Immunologists, 2016-08-12$$n6$$p2421-2433$$tThe Journal of Immunology$$v197$$x0022-1767$$y2016
000138812 773__ $$0PERI:(DE-600)1475085-5$$a10.4049/jimmunol.1600035$$gVol. 197, no. 6, p. 2421 - 2433$$n6$$p2421-2433$$q197:6<2421 - 2433$$tThe journal of immunology$$v197$$x0022-1767$$y2016
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000138812 9131_ $$0G:(DE-HGF)POF3-342$$1G:(DE-HGF)POF3-340$$2G:(DE-HGF)POF3-300$$aDE-HGF$$bForschungsbereich Gesundheit$$lErkrankungen des Nervensystems$$vDisease Mechanisms and Model Systems$$x0
000138812 9141_ $$y2016
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