Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 33, Issue 14, Pages 2760-2772Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01519-12
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Funding
- Translational Research Center for Protein Function Control, NSF, South Korea [2009-0092960]
- National Research Foundation of Korea
- South Korean Government (MEST) [2012002009]
- National Research Foundation of Korea [2009-0092960] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Interleukin-1 beta (IL-1 beta) is a potent proinflammatory and immunoregulatory cytokine playing an important role in the progression of rheumatoid arthritis (RA). However, the signaling network of IL-1 beta 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-1 beta-stimulated synoviocytes, as well as synovium, from RA patients. IL-1 beta enhanced the binding of NF-kappa B and ATF-2 to the PLD1 promoter, thereby enhancing PLD1 expression. PLD1 inhibition abolished the IL-1 beta-induced expression of proinflammatory mediators and angiogenic factors by suppressing the binding of NF-kappa B or hypoxia-inducible factor 1 alpha to the promoter of its target genes, as well as IL-1 beta-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-1 beta-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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