Cutting edge: CIAS1/cryopyrin/PYPAF1/NALP3/CATERPILLER 1.1 is an inducible inflammatory mediator with NF-kappa B suppressive properties.
Mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene have been recently linked to three chronic autoinflammatory disorders. These observations point to an important role for CIAS1 in regulating inflammatory processes. We report that TNF-alpha and ligands recognized by multiple Toll-like receptors rapidly induce CIAS1 gene expression in primary human monocytes. Transfection of full-length CIAS1 or either of two shorter, naturally occurring isoforms dramatically inhibited TNF-alpha-induced activation of NF-kappaB reporter activity. Furthermore, CIAS1 suppressed TNF-alpha-induced nuclear translocation of endogenous p65. Transcriptional activity of exogenous NF-kappaB p65 was also blocked by CIAS1. The nucleotide-binding and leucine-rich repeat regions, but not the pyrin domain of CIAS1, are responsible for this inhibition. These data suggest CIAS1/cryopyrin may act as a key regulator of inflammation, induced to dampen NF-kappaB-dependent proinflammatory signals.
O'Connor
William
W
Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
Harton
Jonathan A
JA
Zhu
Xinsheng
X
Linhoff
Michael W
MW
Ting
Jenny P-Y
JP
D021581:Active Transport, Cell Nucleus / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000595:Amino Acid Sequence; D001798:Blood Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D003593:Cytoplasm / Q000276:immunology / Q000378:metabolism; D017930:Genes, Reporter / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology*; D000090263:Leucine-Rich Repeat Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000502:physiology; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020033:Protein Isoforms / Q000096:biosynthesis / Q000502:physiology; D011506:Proteins / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology; D020449:Repetitive Sequences, Amino Acid; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology
D000276:Adjuvants, Immunologic; D001798:Blood Proteins; D002352:Carrier Proteins; D018836:Inflammation Mediators; D000090263:Leucine-Rich Repeat Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D020033:Protein Isoforms; D011506:Proteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha