Abstract
Familial cold autoinflammatory syndrome (FCAS) and the related autoinflammatory disorders, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, are characterized by mutations in the CIAS1 gene that encodes cryopyrin, an adaptor protein involved in activation of IL-converting enzyme/caspase-1. Mutations in cryopyrin are hypothesized to result in abnormal secretion of caspase-1-dependent proinflammatory cytokines, IL-1beta and IL-18. In this study, we examined cytokine secretion in PBMCs from FCAS patients and found a marked hyperresponsiveness of both IL-1beta and IL-18 secretion to LPS stimulation, but no evidence of increased basal secretion of these cytokines, or alterations in basal or stimulated pro-IL-1beta levels. VX-765, an orally active IL-converting enzyme/caspase-1 inhibitor, blocked IL-1beta secretion with equal potency in LPS-stimulated cells from FCAS and control subjects. These results further link mutations in cryopyrin with abnormal caspase-1 activation, and support the clinical testing of caspase-1 inhibitors such as VX-765 in autoinflammatory disorders.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Autoimmune Diseases / enzymology
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Autoimmune Diseases / genetics
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Autoimmune Diseases / immunology*
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Carrier Proteins / genetics
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Carrier Proteins / physiology
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Caspase 1 / biosynthesis
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Caspase 1 / physiology
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Caspase Inhibitors*
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Cold Temperature / adverse effects*
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Cysteine Proteinase Inhibitors / pharmacology*
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Cytokines / metabolism
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Drug Evaluation, Preclinical
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Female
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Humans
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Hypersensitivity / enzymology
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Hypersensitivity / genetics
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Hypersensitivity / immunology
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Hypersensitivity / prevention & control*
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Inflammation / enzymology
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Inflammation / genetics
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Inflammation / prevention & control
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Interleukin-1 / antagonists & inhibitors
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Interleukin-1 / biosynthesis
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Interleukin-1 / metabolism
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Lipopolysaccharides / pharmacology
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Male
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Middle Aged
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Monocytes / enzymology
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Monocytes / metabolism
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Monocytes / pathology*
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NLR Family, Pyrin Domain-Containing 3 Protein
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Prodrugs / pharmacology
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Protein Precursors / biosynthesis
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Syndrome
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Carrier Proteins
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Caspase Inhibitors
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Cysteine Proteinase Inhibitors
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Cytokines
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Interleukin-1
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Lipopolysaccharides
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NLR Family, Pyrin Domain-Containing 3 Protein
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NLRP3 protein, human
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Prodrugs
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Protein Precursors
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Caspase 1