Abstract
Interleukin-1β (IL-1β) is a potent proinflammatory and immunoregulatory cytokine playing an important role in the progression of rheumatoid arthritis (RA). However, the signaling network of IL-1β in synoviocytes from RA patients is still poorly understood. Here, we show for the first time that phospholipase D1 (PLD1), but not PLD2, is selectively upregulated in IL-1β-stimulated synoviocytes, as well as synovium, from RA patients. IL-1β enhanced the binding of NF-κB and ATF-2 to the PLD1 promoter, thereby enhancing PLD1 expression. PLD1 inhibition abolished the IL-1β-induced expression of proinflammatory mediators and angiogenic factors by suppressing the binding of NF-κB or hypoxia-inducible factor 1α to the promoter of its target genes, as well as IL-1β-induced proliferation or migration. However, suppression of PLD1 activity promoted cell cycle arrest via transactivation of FoxO3a. Furthermore, PLD1 inhibitor significantly suppressed joint inflammation and destruction in IL-1 receptor antagonist-deficient (IL-1Ra(-/-)) mice, a model of spontaneous arthritis. Taken together, these results suggest that the abnormal upregulation of PLD1 may contribute to the pathogenesis of IL-1β-induced chronic arthritis and that a selective PLD1 inhibitor might provide a potential therapeutic molecule for the treatment of chronic inflammatory autoimmune disorders.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Angiogenic Proteins / genetics
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Angiogenic Proteins / metabolism
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Animals
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Arthritis, Rheumatoid / enzymology*
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Arthritis, Rheumatoid / pathology
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Cell Cycle Checkpoints
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Cell Movement
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Cell Proliferation
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Cells, Cultured
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Chronic Disease
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Enzyme Induction
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Enzyme Inhibitors / pharmacology
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Fibroblasts / drug effects
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Fibroblasts / enzymology
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Forkhead Box Protein O3
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Forkhead Transcription Factors / metabolism*
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / physiology
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Inflammation Mediators / metabolism
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Interleukin 1 Receptor Antagonist Protein / deficiency
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Interleukin 1 Receptor Antagonist Protein / genetics
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Interleukin-1beta / physiology*
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Joint Capsule / enzymology
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Joint Capsule / pathology
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MAP Kinase Signaling System
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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NF-kappa B / metabolism*
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Neovascularization, Pathologic / enzymology
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Phospholipase D / antagonists & inhibitors
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Phospholipase D / physiology*
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Phosphorylation
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Promoter Regions, Genetic
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Protein Processing, Post-Translational
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TNF Receptor-Associated Factor 6 / metabolism
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Transcriptional Activation
Substances
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Angiogenic Proteins
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Enzyme Inhibitors
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FOXO3 protein, human
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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IL1B protein, human
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Il1rn protein, mouse
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Inflammation Mediators
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Interleukin 1 Receptor Antagonist Protein
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Interleukin-1beta
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NF-kappa B
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TNF Receptor-Associated Factor 6
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Phospholipase D
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phospholipase D1