Return to homeostasis: downregulation of NF-κB responses
TL;DR: This review highlights key negative regulatory principles that affect the amount, localization or conformational properties of NF-κB-activating proteins to attenuate the NF-kB response to prevent inflammation, autoimmune disease and oncogenesis.
Abstract: Activation of NF-κB transcription factors by receptors of the innate or adaptive immune system is essential for host defense. However, after danger is eliminated, NF-κB signaling needs to be tightly downregulated for the maintenance of tissue homeostasis. This review highlights key negative regulatory principles that affect the amount, localization or conformational properties of NF-κB-activating proteins to attenuate the NF-κB response. These mechanisms are needed to prevent inflammation, autoimmune disease and oncogenesis.
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TL;DR: How the initial discovery of a role for NF-κB in linking inflammation and cancer led to an improved understanding of tumour-elicited inflammation and its effects on anticancer immunity is discussed.
Abstract: Fourteen years have passed since nuclear factor-κB (NF-κB) was first shown to serve as a molecular lynchpin that links persistent infections and chronic inflammation to increased cancer risk. The young field of inflammation and cancer has now come of age, and inflammation has been recognized by the broad cancer research community as a hallmark and cause of cancer. Here, we discuss how the initial discovery of a role for NF-κB in linking inflammation and cancer led to an improved understanding of tumour-elicited inflammation and its effects on anticancer immunity.
1,545 citations
TL;DR: Although it seems to fulfill a distinctly tumor-promoting role in many types of cancer, NF-κB has a confounding role in certain tumors.
Abstract: Inflammation is a fundamental protective response that sometimes goes awry and becomes a major cofactor in the pathogenesis of many chronic human diseases, including cancer. Here we review the evolutionary relationship and opposing functions of the transcription factor NF-κB in inflammation and cancer. Although it seems to fulfill a distinctly tumor-promoting role in many types of cancer, NF-κB has a confounding role in certain tumors. Understanding the activity and function of NF-κB in the context of tumorigenesis is critical for its successful taming, an important challenge for modern cancer biology.
1,242 citations
TL;DR: This work identifies an NF-KappaB Interacting LncRNA (NKILA), which is upregulated by NF-κB, binds to NF-σκB/IκBs, and directly masks phosphorylation motifs of IKKB, thereby inhibiting IKK-induced IκBosphorylation and NF-kkB activation.
723 citations
Cites background from "Return to homeostasis: downregulati..."
...Different frommost previously identified NF-kB suppressors that either inhibit signaling upstream of IKK complex or affect the amount of NF-kB or IkB (Ruland, 2011; Tse et al., 2007), NKILA operates at the level of IkB by directly inhibiting IKK-induced IkB phosphorylation without influencing IKK activity, which represents a different layer of negative regulation on NF-kB pathway....
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...…frommost previously identified NF-kB suppressors that either inhibit signaling upstream of IKK complex or affect the amount of NF-kB or IkB (Ruland, 2011; Tse et al., 2007), NKILA operates at the level of IkB by directly inhibiting IKK-induced IkB phosphorylation without influencing IKK…...
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...A number of negative regulators for NF-kB pathway, for example deubiquitinase (DUB) A20 (Cake et al., 2003) and CYLD (Brummelkamp et al., 2003), ubiquitin ligase SOCS-1 (Ruland, 2011), and a group of miRNAs (Boldin and Baltimore, 2012), etc, have been shown to be tumor suppressors....
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...Nuclear factor-kB (NF-kB) is a family of transcription factors that play critical roles in inflammation, immunity, cell proliferation, differentiation, and survival (Ruland, 2011)....
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..., 2003), ubiquitin ligase SOCS-1 (Ruland, 2011), and a group of miRNAs (Boldin and Baltimore, 2012), etc, have been shown to be tumor suppressors....
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TL;DR: The authors explored general mechanisms of TNF cytokine signaling, with a focus on the upstream signaling events leading to activation of the so-called canonical and non-canonical NF-κB pathways by TNFR1 and CD40, respectively.
681 citations
TL;DR: This Review describes the development of curcumin from a "traditional" spice and food coloring to a "modern" biological regulator.
Abstract: Turmeric is traditionally used as a spice and coloring in foods. It is an important ingredient in curry and gives curry powder its characteristic yellow color. As a consequence of its intense yellow color, turmeric, or curcumin (food additive E100), is used as a food coloring (e.g. mustard). Turmeric contains the curcuminoids curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Recently, the health properties (neuroprotection, chemo-, and cancer prevention) of curcuminoids have gained increasing attention. Curcuminoids induce endogenous antioxidant defense mechanisms in the organism and have anti-inflammatory activity. Curcuminoids influence gene expression as well as epigenetic mechanisms. Synthetic curcumin analogues also exhibit biological activity. This Review describes the development of curcumin from a "traditional" spice and food coloring to a "modern" biological regulator.
639 citations
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TL;DR: Recent advances that have been made by research into the role of TLR biology in host defense and disease are described.
Abstract: The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.
7,494 citations
TL;DR: The authors synthesize some of the basic principles that have emerged from studies of NF-kappaB, and aim to generate a more unified view of the regulation of the transcription factor.
3,996 citations
TL;DR: A role is proposed for miR-146 in control of Toll-like receptor and cytokine signaling through a negative feedback regulation loop involving down-regulation of IL-1 receptor-associated kinase 1 and TNF receptor- associated factor 6 protein levels.
Abstract: Activation of mammalian innate and acquired immune responses must be tightly regulated by elaborate mechanisms to control their onset and termination. MicroRNAs have been implicated as negative regulators controlling diverse biological processes at the level of posttranscriptional repression. Expression profiling of 200 microRNAs in human monocytes revealed that several of them (miR-146a/b, miR-132, and miR-155) are endotoxin-responsive genes. Analysis of miR-146a and miR-146b gene expression unveiled a pattern of induction in response to a variety of microbial components and proinflammatory cytokines. By means of promoter analysis, miR-146a was found to be a NF-κB-dependent gene. Importantly, miR-146a/b were predicted to base-pair with sequences in the 3′ UTRs of the TNF receptor-associated factor 6 and IL-1 receptor-associated kinase 1 genes, and we found that these UTRs inhibit expression of a linked reporter gene. These genes encode two key adapter molecules downstream of Toll-like and cytokine receptors. Thus, we propose a role for miR-146 in control of Toll-like receptor and cytokine signaling through a negative feedback regulation loop involving down-regulation of IL-1 receptor-associated kinase 1 and TNF receptor-associated factor 6 protein levels.
3,947 citations
TL;DR: How genetic evidence in mice has revealed complex roles for the NF-kappaB in inflammation that suggest both pro- and anti-inflammatory roles for this pathway is described.
Abstract: The nuclear factor NF-κB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-κB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules In this article, we describe how genetic evidence in mice has revealed complex roles for the NF-κB in inflammation that suggest both pro- and anti-inflammatory roles for this pathway NF-κB has long been considered the “holy grail” as a target for new anti-inflammatory drugs; however, these recent studies suggest this pathway may prove a difficult target in the treatment of chronic disease In this article, we discuss the role of NF-κB in inflammation in light of these recent studies
3,396 citations
TL;DR: Much progress has been made in the past two years revealing new insights into the regulation and functions of NF-kappaB, and this recent progress is covered in this review.
Abstract: The mammalian Rel/NF-κB family of transcription factors, including RelA, c-Rel, RelB, NF-κB1 (p50 and its precursor p105), and NF-κB2 (p52 and its precursor p100), plays a central role in the immune system by regulating several processes ranging from the development and survival of lymphocytes and lymphoid organs to the control of immune responses and malignant transformation. The five members of the NF-κB family are normally kept inactive in the cytoplasm by interaction with inhibitors called IκBs or the unprocessed forms of NF-κB1 and NF-κB2. A wide variety of signals emanating from antigen receptors, pattern-recognition receptors, receptors for the members of TNF and IL-1 cytokine families, and others induce differential activation of NF-κB heterodimers. Although work over the past two decades has shed significant light on the regulation of NF-κB transcription factors and their functions, much progress has been made in the past two years revealing new insights into the regulation and functions of NF-κB...
2,380 citations