Phospholipase d1 has a pivotal role in interleukin-1βdriven chronic autoimmune arthritis through regulation of NF-κB, hypoxia-inducible factor 1α, and foxo3a

Dong Woo Kang, Mi Kyung Park, Hye Joa Oh, Dong Gun Lee, Sung Hwan Park, Mi La Cho, Kang Yell Choi, Do Sik Min

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 (PLD1β), but not PLD2, is selectively upregulated in IL-1β-stimulated synoviocytes, as well as synovium, from RA patients. IL-1β enhanced the binding of NFΚB 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 NFΚB 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.

Original languageEnglish
Pages (from-to)2760-2772
Number of pages13
JournalMolecular and Cellular Biology
Volume33
Issue number14
DOIs
Publication statusPublished - 2013 Jul 1

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Hypoxia-Inducible Factor 1
Interleukins
Arthritis
Interleukin-1
Rheumatoid Arthritis
Interleukin-1 Receptors
phospholipase D1
Synovial Membrane
Angiogenesis Inducing Agents
Cell Cycle Checkpoints
Transcriptional Activation
Up-Regulation
Joints
Cytokines
Inflammation
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

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title = "Phospholipase d1 has a pivotal role in interleukin-1βdriven 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 (PLD1β), but not PLD2, is selectively upregulated in IL-1β-stimulated synoviocytes, as well as synovium, from RA patients. IL-1β enhanced the binding of NFΚB 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 NFΚB 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.",
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Phospholipase d1 has a pivotal role in interleukin-1βdriven chronic autoimmune arthritis through regulation of NF-κB, hypoxia-inducible factor 1α, and foxo3a. / Kang, Dong Woo; Park, Mi Kyung; Oh, Hye Joa; Lee, Dong Gun; Park, Sung Hwan; Cho, Mi La; Choi, Kang Yell; Min, Do Sik.

In: Molecular and Cellular Biology, Vol. 33, No. 14, 01.07.2013, p. 2760-2772.

Research output: Contribution to journalArticle

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AU - Kang, Dong Woo

AU - Park, Mi Kyung

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N2 - 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 (PLD1β), but not PLD2, is selectively upregulated in IL-1β-stimulated synoviocytes, as well as synovium, from RA patients. IL-1β enhanced the binding of NFΚB 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 NFΚB 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.

AB - 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 (PLD1β), but not PLD2, is selectively upregulated in IL-1β-stimulated synoviocytes, as well as synovium, from RA patients. IL-1β enhanced the binding of NFΚB 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 NFΚB 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.

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