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Non-canonical NF-κB signaling in rheumatoid arthritis: Dr Jekyll and Mr Hyde?

Noort AR, Tak PP, Tas SW - Arthritis Res. Ther. (2015)

Bottom Line: NF-κB can be activated via two distinct pathways: the classical or canonical pathway, and the alternative or non-canonical pathway.It is well established that the canonical NF-κB pathway is essential both in acute inflammatory responses and in chronic inflammatory diseases, including rheumatoid arthritis (RA).In addition, we discuss current drugs targeting this pathway, as well as future therapeutic prospects.

View Article: PubMed Central - PubMed

ABSTRACT
The nuclear factor-κB (NF-κB) family of transcription factors is essential for the expression of pro-inflammatory cytokines, but can also induce regulatory pathways. NF-κB can be activated via two distinct pathways: the classical or canonical pathway, and the alternative or non-canonical pathway. It is well established that the canonical NF-κB pathway is essential both in acute inflammatory responses and in chronic inflammatory diseases, including rheumatoid arthritis (RA). Although less extensively studied, the non-canonical NF-κB pathway is not only central in lymphoid organ development and adaptive immune responses, but is also thought to play an important role in the pathogenesis of RA. Importantly, this pathway appears to have cell type-specific functions and, since many different cell types are involved in the pathogenesis of RA, it is difficult to predict the net overall contribution of the non-canonical NF-κB pathway to synovial inflammation. In this review, we describe the current understanding of non-canonical NF-κB signaling in various important cell types in the context of RA and consider the relevance to the pathogenesis of the disease. In addition, we discuss current drugs targeting this pathway, as well as future therapeutic prospects.

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Overview of nuclear factor-κB activation pathways. Schematic representation of the canonical and non-canonical nuclear factor (NF)-κB pathways. The canonical NF-κB pathway can be activated by a variety of different stimuli, like tumor necrosis factor-α and lipopolysaccharide (LPS). Activation of the canonical pathway via Toll-like receptor or cytokine receptor signaling depends on the inhibitor of κB kinase (IKK) complex, which is composed of the kinases IKKα and IKKβ, and the regulatory subunit IKKγ (NEMO). Activated IKK phosphorylates the inhibitory subunit IκBα to induce its degradation, allowing NF-κB dimers (p50-p65) to translocate to the nucleus and bind to DNA to induce NF-κB target gene transcription. The non-canonical pathway (right) is activated by specific stimuli like B cell activating factor, lymphotoxin β, LIGHT and CD40L. NF-κB inducing kinase (NIK) is stabilized and activates and recruits IKKα into the p100 complex to phosphorylate p100, leading to p100 ubiquitination. Processing of p100 generates the p52/RelB NF-κB complex, which is able to translocate to the nucleus and induce gene expression.
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Fig1: Overview of nuclear factor-κB activation pathways. Schematic representation of the canonical and non-canonical nuclear factor (NF)-κB pathways. The canonical NF-κB pathway can be activated by a variety of different stimuli, like tumor necrosis factor-α and lipopolysaccharide (LPS). Activation of the canonical pathway via Toll-like receptor or cytokine receptor signaling depends on the inhibitor of κB kinase (IKK) complex, which is composed of the kinases IKKα and IKKβ, and the regulatory subunit IKKγ (NEMO). Activated IKK phosphorylates the inhibitory subunit IκBα to induce its degradation, allowing NF-κB dimers (p50-p65) to translocate to the nucleus and bind to DNA to induce NF-κB target gene transcription. The non-canonical pathway (right) is activated by specific stimuli like B cell activating factor, lymphotoxin β, LIGHT and CD40L. NF-κB inducing kinase (NIK) is stabilized and activates and recruits IKKα into the p100 complex to phosphorylate p100, leading to p100 ubiquitination. Processing of p100 generates the p52/RelB NF-κB complex, which is able to translocate to the nucleus and induce gene expression.

Mentions: The most extensively studied NF-κB activation pathway is the canonical pathway (Figure 1), which can be activated by stimulation of a variety of cell membrane receptors, including tumor necrosis factor (TNF) receptor, interleukin (IL)-1 receptor, and Toll-like receptors, in response to pro-inflammatory stimuli like lipopolysaccharide, IL-1 and TNF, as well as via triggering of the T-cell receptor or B-cell receptor. In this pathway, inhibitor of κB kinase (IKK)β is required for NF-κB activation, whereas IKKα is redundant [4]. The canonical NF-κB pathway is essential both in acute inflammatory responses and in chronic inflammatory diseases such as RA and inflammatory bowel disease. Moreover, this pathway is important in cell proliferation and survival, demonstrated by constitutively active NF-κB signaling in many tumor tissues [5]. In RA IKKβ is a key regulator of synovial inflammation [6] and the importance of the canonical NF-κB pathway in arthritis is underlined by the beneficial effects of specific IKKβ inhibition in preclinical models of arthritis [6,7] and the common and successful use of anti-TNF therapy in RA, one of the main target genes of the canonical NF-κB pathway. This is outside the scope of the current review, however, but is discussed in more detail in previous reviews [2,3]. Here we focus on the alternative or non-canonical NF-κB pathway.Figure 1


Non-canonical NF-κB signaling in rheumatoid arthritis: Dr Jekyll and Mr Hyde?

Noort AR, Tak PP, Tas SW - Arthritis Res. Ther. (2015)

Overview of nuclear factor-κB activation pathways. Schematic representation of the canonical and non-canonical nuclear factor (NF)-κB pathways. The canonical NF-κB pathway can be activated by a variety of different stimuli, like tumor necrosis factor-α and lipopolysaccharide (LPS). Activation of the canonical pathway via Toll-like receptor or cytokine receptor signaling depends on the inhibitor of κB kinase (IKK) complex, which is composed of the kinases IKKα and IKKβ, and the regulatory subunit IKKγ (NEMO). Activated IKK phosphorylates the inhibitory subunit IκBα to induce its degradation, allowing NF-κB dimers (p50-p65) to translocate to the nucleus and bind to DNA to induce NF-κB target gene transcription. The non-canonical pathway (right) is activated by specific stimuli like B cell activating factor, lymphotoxin β, LIGHT and CD40L. NF-κB inducing kinase (NIK) is stabilized and activates and recruits IKKα into the p100 complex to phosphorylate p100, leading to p100 ubiquitination. Processing of p100 generates the p52/RelB NF-κB complex, which is able to translocate to the nucleus and induce gene expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4308835&req=5

Fig1: Overview of nuclear factor-κB activation pathways. Schematic representation of the canonical and non-canonical nuclear factor (NF)-κB pathways. The canonical NF-κB pathway can be activated by a variety of different stimuli, like tumor necrosis factor-α and lipopolysaccharide (LPS). Activation of the canonical pathway via Toll-like receptor or cytokine receptor signaling depends on the inhibitor of κB kinase (IKK) complex, which is composed of the kinases IKKα and IKKβ, and the regulatory subunit IKKγ (NEMO). Activated IKK phosphorylates the inhibitory subunit IκBα to induce its degradation, allowing NF-κB dimers (p50-p65) to translocate to the nucleus and bind to DNA to induce NF-κB target gene transcription. The non-canonical pathway (right) is activated by specific stimuli like B cell activating factor, lymphotoxin β, LIGHT and CD40L. NF-κB inducing kinase (NIK) is stabilized and activates and recruits IKKα into the p100 complex to phosphorylate p100, leading to p100 ubiquitination. Processing of p100 generates the p52/RelB NF-κB complex, which is able to translocate to the nucleus and induce gene expression.
Mentions: The most extensively studied NF-κB activation pathway is the canonical pathway (Figure 1), which can be activated by stimulation of a variety of cell membrane receptors, including tumor necrosis factor (TNF) receptor, interleukin (IL)-1 receptor, and Toll-like receptors, in response to pro-inflammatory stimuli like lipopolysaccharide, IL-1 and TNF, as well as via triggering of the T-cell receptor or B-cell receptor. In this pathway, inhibitor of κB kinase (IKK)β is required for NF-κB activation, whereas IKKα is redundant [4]. The canonical NF-κB pathway is essential both in acute inflammatory responses and in chronic inflammatory diseases such as RA and inflammatory bowel disease. Moreover, this pathway is important in cell proliferation and survival, demonstrated by constitutively active NF-κB signaling in many tumor tissues [5]. In RA IKKβ is a key regulator of synovial inflammation [6] and the importance of the canonical NF-κB pathway in arthritis is underlined by the beneficial effects of specific IKKβ inhibition in preclinical models of arthritis [6,7] and the common and successful use of anti-TNF therapy in RA, one of the main target genes of the canonical NF-κB pathway. This is outside the scope of the current review, however, but is discussed in more detail in previous reviews [2,3]. Here we focus on the alternative or non-canonical NF-κB pathway.Figure 1

Bottom Line: NF-κB can be activated via two distinct pathways: the classical or canonical pathway, and the alternative or non-canonical pathway.It is well established that the canonical NF-κB pathway is essential both in acute inflammatory responses and in chronic inflammatory diseases, including rheumatoid arthritis (RA).In addition, we discuss current drugs targeting this pathway, as well as future therapeutic prospects.

View Article: PubMed Central - PubMed

ABSTRACT
The nuclear factor-κB (NF-κB) family of transcription factors is essential for the expression of pro-inflammatory cytokines, but can also induce regulatory pathways. NF-κB can be activated via two distinct pathways: the classical or canonical pathway, and the alternative or non-canonical pathway. It is well established that the canonical NF-κB pathway is essential both in acute inflammatory responses and in chronic inflammatory diseases, including rheumatoid arthritis (RA). Although less extensively studied, the non-canonical NF-κB pathway is not only central in lymphoid organ development and adaptive immune responses, but is also thought to play an important role in the pathogenesis of RA. Importantly, this pathway appears to have cell type-specific functions and, since many different cell types are involved in the pathogenesis of RA, it is difficult to predict the net overall contribution of the non-canonical NF-κB pathway to synovial inflammation. In this review, we describe the current understanding of non-canonical NF-κB signaling in various important cell types in the context of RA and consider the relevance to the pathogenesis of the disease. In addition, we discuss current drugs targeting this pathway, as well as future therapeutic prospects.

Show MeSH
Related in: MedlinePlus