ArticleThe Journal of biological chemistry2015
Prolyl-4-hydroxylase domain protein 2 controls NF-κB/p65 transactivation and enhances the catabolic effects of inflammatory cytokines on cells of the nucleus pulposus.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 49 citations in OpenAlex.
- POSTN knockdown suppresses IL-1β-induced inflammation and apoptosis of nucleus pulposus cells via inhibiting the NF-κB pathway and alleviates intervertebral disc degeneration.Journal of cell communication and signaling · 2024Article
- Maslinic acid alleviates intervertebral disc degeneration by inhibiting the PI3K/AKT and NF-κB signaling pathways.Acta biochimica et biophysica Sinica · 2024Article
- Prolyl hydroxylase 2 inhibits glycolytic activity in colorectal cancer via the NF‑κB signaling pathway.International journal of oncology · 2024Article
- Inflammation in Pulmonary Hypertension and Edema Induced by Hypobaric Hypoxia Exposure.International journal of molecular sciences · 2022Review
- Extracellular matrix in intervertebral disc: basic and translational implications.Cell and tissue research · 2022Review
- Review
- The role of oxidative stress in intervertebral disc cellular senescence.Frontiers in endocrinology · 2022Review
- Aloin Regulates Matrix Metabolism and Apoptosis in Human Nucleus Pulposus Cells via the TAK1/NF-Stem cells international · 2022Article
- Chronic and Cycling Hypoxia: Drivers of Cancer Chronic Inflammation through HIF-1 and NF-κB Activation: A Review of the Molecular Mechanisms.International journal of molecular sciences · 2021Review
- NF-κB signalling pathways in nucleus pulposus cell function and intervertebral disc degeneration.Cell proliferation · 2021Review
- What Are the Potential Roles of Nuclear Perlecan and Other Heparan Sulphate Proteoglycans in the Normal and Malignant Phenotype.International journal of molecular sciences · 2021Review
- Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research.International journal of molecular sciences · 2021Review
- Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development.The Journal of pathology · 2020Article
- Angiopoietin-like protein 8 expression and association with extracellular matrix metabolism and inflammation during intervertebral disc degeneration.Journal of cellular and molecular medicine · 2019Article
- Prolyl hydroxylase inhibitor DMOG suppressed inflammatory cytokine production in human gingival fibroblasts stimulated with Fusobacterium nucleatum.Clinical oral investigations · 2019Article
- Article
- Review
- Prolyl hydroxylases positively regulated LPS-induced inflammation in human gingival fibroblasts via TLR4/MyD88-mediated AKT/NF-κB and MAPK pathways.Cell proliferation · 2018Article
- ADAMTS5 Deficiency Protects Mice From Chronic Tobacco Smoking-induced Intervertebral Disc Degeneration.Spine · 2017Article
- PHD3 is a transcriptional coactivator of HIF-1α in nucleus pulposus cells independent of the PKM2-JMJD5 axis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Prolyl-4-hydroxylase (PHD) proteins are key in sensing tissue hypoxia. In nucleus pulposus (NP) cells, our previous work demonstrated that PHD isoforms have a differential contribution in controlling hypoxia-inducible factor (HIF)-α degradation and activity. Recently we have shown that a regulatory relationship exists between PHD3 and inflammatory cytokines in NP cells. With respect to PHD2, the most abundant PHD isoform in NP cells, very little is known concerning its function and regulation under inflammatory conditions that characterize intervertebral disc degeneration. Here, we show that PHD2 is a potent regulator of the catabolic activities of TNF-α; silencing of PHD2 significantly decreased TNF-α-induced expression of catabolic markers including SDC4, MMP-3, MMP-13, and ADAMTS5, as well as several inflammatory cytokines and chemokines, while partially restoring aggrecan and collagen II expression. Use of NF-κB reporters with ShPHD2, SiHIF-1α, as well as p65(-/-), PHD2(-/-), and PHD3(-/-) cells, shows that PHD2 serves as a co-activator of NF-κB/p65 signaling in HIF-1-independent fashion. Immunoprecipitation of endogenous and exogenously expressed tagged proteins, as well as fluorescence microscopy, indicates that following TNF-α treatment, PHD2 interacts and co-localizes with p65. Conversely, loss of function experiments using lentivirally delivered Sh-p65, Sh-IKKβ, and NF-κB inhibitor confirmed that cytokine-dependent PHD2 expression in NP cells requires NF-κB signaling. These findings clearly demonstrate that PHD2 forms a regulatory circuit with TNF-α via NF-κB and thereby plays an important role in enhancing activity of this cytokine. We propose that during disc degeneration PHD2 may offer a therapeutic target to mitigate the deleterious actions of TNF-α, a key proinflammatory cytokine.
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