| First Author | Kang DW | Year | 2013 |
| Journal | Mol Cell Biol | Volume | 33 |
| Issue | 14 | Pages | 2760-72 |
| PubMed ID | 23689131 | Mgi Jnum | J:204478 |
| Mgi Id | MGI:5532630 | Doi | 10.1128/MCB.01519-12 |
| Citation | Kang DW, et al. (2013) Phospholipase D1 has a pivotal role in interleukin-1beta-driven chronic autoimmune arthritis through regulation of NF-kappaB, hypoxia-inducible factor 1alpha, and FoxO3a. Mol Cell Biol 33(14):2760-72 |
| abstractText | Interleukin-1beta (IL-1beta) is a potent proinflammatory and immunoregulatory cytokine playing an important role in the progression of rheumatoid arthritis (RA). However, the signaling network of IL-1beta 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-1beta-stimulated synoviocytes, as well as synovium, from RA patients. IL-1beta enhanced the binding of NF-kappaB and ATF-2 to the PLD1 promoter, thereby enhancing PLD1 expression. PLD1 inhibition abolished the IL-1beta-induced expression of proinflammatory mediators and angiogenic factors by suppressing the binding of NF-kappaB or hypoxia-inducible factor 1alpha to the promoter of its target genes, as well as IL-1beta-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-1beta-induced chronic arthritis and that a selective PLD1 inhibitor might provide a potential therapeutic molecule for the treatment of chronic inflammatory autoimmune disorders. |
