title: Phospholipase D1 has a pivotal role in interleukin-1β-driven chronic autoimmune arthritis through regulation of NF-κB, hypoxia-inducible factor 1α, and FoxO3a.
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.
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea.
authors.forename: Dong Woo
authors.initials: DW
authors.lastname: Kang
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Park
authors.forename: Hye-Joa
authors.initials: HJ
authors.lastname: Oh
authors.forename: Dong-Gun
authors.initials: DG
authors.lastname: Lee
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
authors.forename: Kang-Yell
authors.initials: KY
authors.lastname: Choi
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.forename: Do Sik
authors.initials: do S
authors.lastname: Min
mesh_terms: D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000473:pathology; D059447:Cell Cycle Checkpoints; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002908:Chronic Disease; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000172:deficiency / Q000235:genetics; D053583:Interleukin-1beta / Q000502:physiology*; D017746:Joint Capsule / Q000201:enzymology / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000201:enzymology; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D042501:Angiogenic Proteins; D004791:Enzyme Inhibitors; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C508585:IL1B protein, human; C507764:Il1rn protein, mouse; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D010739:Phospholipase D; C106801:phospholipase D1