Abstract
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.
MeSH terms
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Active Transport, Cell Nucleus / immunology
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Adjuvants, Immunologic / pharmacology
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Amino Acid Sequence
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Blood Proteins / biosynthesis
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Blood Proteins / genetics
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Blood Proteins / physiology*
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Carrier Proteins / biosynthesis
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Cell Nucleus / immunology
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Cell Nucleus / metabolism
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Cytoplasm / immunology
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Cytoplasm / metabolism
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Genes, Reporter / immunology
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HeLa Cells
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Humans
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Inflammation Mediators / metabolism
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Inflammation Mediators / pharmacology*
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Leucine-Rich Repeat Proteins
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Lipopolysaccharides / pharmacology
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Membrane Glycoproteins / physiology
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Molecular Sequence Data
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Monocytes / immunology
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Monocytes / metabolism
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / genetics
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NF-kappa B / metabolism
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NLR Family, Pyrin Domain-Containing 3 Protein
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Protein Isoforms / biosynthesis
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Protein Isoforms / physiology
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Proteins / physiology
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Receptors, Cell Surface / physiology
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Repetitive Sequences, Amino Acid
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Signal Transduction / immunology
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Toll-Like Receptors
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / pharmacology
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Tumor Necrosis Factor-alpha / physiology
Substances
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Adjuvants, Immunologic
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Blood Proteins
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Carrier Proteins
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Inflammation Mediators
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Leucine-Rich Repeat Proteins
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Lipopolysaccharides
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Membrane Glycoproteins
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NF-kappa B
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NLR Family, Pyrin Domain-Containing 3 Protein
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NLRP3 protein, human
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Protein Isoforms
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Proteins
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Receptors, Cell Surface
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Toll-Like Receptors
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha