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

Li, Jun; Wen, Yan; Jiang, Shuai; Ye, Wei; Yang, Hao; Shapiro, Irving M.; Risbud, Makarand V.

doi:10.1074/jbc.m114.611483

Cited by 52 publications

(47 citation statements)

References 43 publications

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“…Importantly, TLR2 activation provides another mechanism for activating p38, ERK1/2, and NF-B signaling during disc degeneration. Furthermore, phosphorylation of NF-B is sustained (Ͼ30 min), which agrees with other studies that have found prolonged NF-B activation in NP and AF cells (46,47). For other pathologies, both p38 (rheumatoid arthritis) and NF-B (atopic dermatitis) inhibitors have gone to clinical trials (45).…”

Section: Tlr2 Regulates Ngf Via Nf-bsupporting

confidence: 78%

Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

Krock

Currie

Weber

et al. 2016

Journal of Biological Chemistry

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Nerve growth factor (NGF) contributes to the development of chronic pain associated with degenerative connective tissue pathologies, such as intervertebral disc degeneration and osteoarthritis. However, surprisingly little is known about the regulation of NGF in these conditions. Toll-like receptors (TLR) are pattern recognition receptors classically associated with innate immunity but more recently were found to be activated by endogenous alarmins such as fragmented extracellular matrix proteins found in degenerating discs or cartilage. In this study we investigated if TLR activation regulates NGF and which signaling mechanisms control this response in intervertebral discs. TLR2 agonists, TLR4 agonists, or IL-1␤ (control) treatment increased NGF, brain-derived neurotrophic factor (BDNF), and IL-1␤ gene expression in human disc cells isolated from healthy, pain-free organ donors. However, only TLR2 activation or IL-1␤ treatment increased NGF protein secretion. TLR2 activation increased p38, ERK1/2, and p65 activity and increased p65 translocation to the cell nucleus. JNK activity was not affected by TLR2 activation. Inhibition of NF-B, and to a lesser extent p38, but not ERK1/2 activity, blocked TLR2-driven NGF up-regulation at both the transcript and protein levels. These results provide a novel mechanism of NGF regulation in the intervertebral disc and potentially other pathogenic connective tissues. TLR2 and NF-B signaling are known to increase cytokines and proteases, which accelerate matrix degradation. Therefore, TLR2 or NF-B inhibition may both attenuate chronic pain and slow the degenerative progress in vivo.

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Section: Tlr2 Regulates Ngf Via Nf-bsupporting

confidence: 78%

Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

Krock

Currie

Weber

et al. 2016

Journal of Biological Chemistry

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“…Conversely, another group has found that PHD3 inhibits NF-κB by a prolyl hydroxylase-independent inhibition of IKKγ ubiquitination [92]. In addition, a cooperative role of PHD2 with respect to NF-κB activity, functioning as coactivator of p65, has been shown [94]. Taken together, these studies exemplify the cell type and context specificity of hypoxia induced NF-κB regulation by PHDs.…”

Section: Role Of the Oxygen Sensors In The Hypoxia Induction Of Nf-κbsupporting

confidence: 49%

Hypoxia and Inflammation in Cancer, Focus on HIF and NF-кB

D'Ignazio¹,

Batie²,

Rocha³

2017

Preprint

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Cancer is often characterised by the presence of hypoxia and inflammation.Paramount to the mechanisms controlling cellular responses under such stress stimuli, are the transcription factor families of Hypoxia Inducible Factor (HIF) and NuclearFactor of kappa-light-chain-enhancer of activated B cells (NF-κB). Although, a detailed understating of how these transcription factors respond to their cognate stimulus is well established, it is now appreciated that HIF and NF-κB undergo extensive crosstalk, in particular in pathological situations such as cancer. Here, we focus on the current knowledge on how HIF is activated by inflammation and how NF-κB is modulated by hypoxia. We summarise the evidence for the possible mechanism behind this activation and how HIF and NF-κB function impacts cancer, focusing on colorectal, breast and lung cancer. We discuss possible new points of therapeutic intervention aiming to harness the current understanding of the HIF-NF-κB crosstalk.

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“…Li et al [73] found that prolyl hydroxylase (PHD) 2 functions as a co-activator of NF-κB p65 to promote matrix catabolism induced by TNF-α. Exposure of NP cells to TNF-α up-regulates the expression of PHD2, which then interacts with NF-κB p65 to stimulate the transcription of MMP-3, MMP-13, and ADAMTS-5 [73]. Similar to PHD2, PHD3 plays a significant role in promoting TNF-α-induced activation of NF-κB and subsequent synthesis of ADAMTS-5 and MMP-13 [74].…”

Section: Tnf-α Promotes Ecm Degradationmentioning

confidence: 99%

Tumor necrosis factor-α: a key contributor to intervertebral disc degeneration

Wang¹,

Yu²,

Yan³

et al. 2017

ABBS

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Intervertebral disc (IVD) degeneration (IDD) is the most common cause leading to low back pain (LBP), which is a highly prevalent, costly, and crippling condition worldwide. Current treatments for IDD are limited to treat the symptoms and do not target the pathophysiology. Tumor necrosis factor-α (TNF-α) is one of the most potent pro-inflammatory cytokines and signals through its receptors TNFR1 and TNFR2. TNF-α is highly expressed in degenerative IVD tissues, and it is deeply involved in multiple pathological processes of disc degeneration, including matrix destruction, inflammatory responses, apoptosis, autophagy, and cell proliferation. Importantly, anti-TNF-α therapy has shown promise for mitigating disc degeneration and relieving LBP. In this review, following a brief description of TNF-α signal transduction, we mainly focus on the expression pattern and roles of TNF-α in IDD, and summarize the emerging progress regarding its inhibition as a promising biological therapeutic approach to disc degeneration and associated LBP. A better understanding will help to develop novel TNF-α-centered therapeutic interventions for degenerative disc disease.

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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

Cited by 52 publications

References 43 publications

Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

Hypoxia and Inflammation in Cancer, Focus on HIF and NF-кB

Tumor necrosis factor-α: a key contributor to intervertebral disc degeneration

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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

Cited by 52 publications

References 43 publications

Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

Hypoxia and Inflammation in Cancer, Focus on HIF and NF-кB

Tumor necrosis factor-&alpha;: a key contributor to intervertebral disc degeneration

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Tumor necrosis factor-α: a key contributor to intervertebral disc degeneration