IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients.

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.

• Authors: Jeffrey H Stack, Kevin Beaumont, Paul D Larsen, Kimberly S Straley, Greg W Henkel, John C R Randle, Hal M Hoffman
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 175 Issue 4 Pg. 2630-4 (Aug 15 2005) ISSN: 0022-1767 [Print] United States
• PMID: 16081838 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Carrier Proteins
• Caspase Inhibitors
• Cysteine Proteinase Inhibitors
• Cytokines
• Interleukin-1
• Lipopolysaccharides
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• Prodrugs
• Protein Precursors
• Caspase 1

Topics

• Adult
• Aged
• Aged, 80 and over
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Autoimmune Diseases (enzymology, genetics, immunology)
• Carrier Proteins (genetics, physiology)
• Caspase 1 (biosynthesis, physiology)
• Caspase Inhibitors
• Cold Temperature (adverse effects)
• Cysteine Proteinase Inhibitors (pharmacology)
• Cytokines (metabolism)
• Drug Evaluation, Preclinical
• Female
• Humans
• Hypersensitivity (enzymology, genetics, immunology, prevention & control)
• Inflammation (enzymology, genetics, prevention & control)
• Interleukin-1 (antagonists & inhibitors, biosynthesis, metabolism)
• Lipopolysaccharides (pharmacology)
• Male
• Middle Aged
• Monocytes (enzymology, metabolism, pathology)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Prodrugs (pharmacology)
• Protein Precursors (biosynthesis)
• Syndrome