Note: The following text is a transcription of the Stone Engraving of the parchment Declaration of Independence (the document on display in the Rotunda at the National Archives Museum.) The spelling and punctuation reflects the original.
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For abolishing the free System of English Laws in a neighbouring Province, establishing therein an Arbitrary government, and enlarging its Boundaries so as to render it at once an example and fit instrument for introducing the same absolute rule into these Colonies:
In every stage of these Oppressions We have Petitioned for Redress in the most humble terms: Our repeated Petitions have been answered only by repeated injury. A Prince whose character is thus marked by every act which may define a Tyrant, is unfit to be the ruler of a free people.
NF-κB target genes involved in inflammation development and progression. NF-κB is an inducible transcription factor. After its activation, it can activate transcription of various genes and thereby regulate inflammation. NF-κB target inflammation not only directly by increasing the production of inflammatory cytokines, chemokines and adhesion molecules, but also regulating the cell proliferation, apoptosis, morphogenesis and differentiation.
The pro-inflammatory function of NF-κB has been extensively studied in macrophages, a large family of innate immune cells that reside in different tissues and function in the front line of an immune response against infections.28 In response to diverse PAMPs and DAMPs, macrophages become rapidly activated and secrete a large array of cytokines and chemokines. Under different pathophysiologic conditions, activated macrophages are capable of differentiating into phenotypically different states, including the classically activated (M1) and the alternatively activated (M2) macrophages.29,30 M1 macrophages are characterized by the production of pro-inflammatory cytokines, such as IL-1, IL-6, IL-12, TNF-α and chemokines, involved in various inflammatory processes. The M1 macrophages also promote the differentiation of inflammatory T cells, including Th1 and Th17 cells, which in turn mediate inflammation.30,31 In contrast, M2 macrophages produce anti-inflammatory cytokines, such as IL-10 and IL-13, and are important for resolution of inflammation and mediating wound healing.32 TLR signals have an important role in regulating macrophage polarization.30 In particular, the TLR4 ligand lipopolysaccharide (LPS) promotes macrophage differentiation toward M1 phenotype.24 LPS stimulates macrophage signaling via two different TLR adapters, MyD88 and TRIF.24 Genetic evidence suggests that the MyD88-dependent TLR pathway is crucial for M1 macrophage polarization and inducible expression of pro-inflammatory cytokines.33 The MyD88-dependent TLR signaling involves activation of IRAK family of kinases, which in turn stimulate the E3 ubiquitin ligase activity of TRAF6, allowing TRAF6 to undergo self-ubiquitination and to conjugate ubiquitin chains onto other signaling molecules that are involved in the activation of a ubiquitin-dependent kinase, TAK1.24,25 Upon activation, TAK1 activates the downstream kinase IKK, which in turn phosphorylate the NF-κB inhibitor IκBα, leading to ubiquitin-dependent IκBα degradation and NF-κB activation.27 NF-κB is a key transcription factor of M1 macrophages and is required for induction of a large number of inflammatory genes, including those encoding TNF-α, IL-1β, IL-6, IL-12p40 and cyclooxygenase-2.30
Canonical NF-κB regulates CD4+ T-cell differentiation via both regulation of cytokine production in innate immune cells and T-cell intrinsic mechanisms. Inhibition of NF-κB in T cells by transgenic expression of a degradation-resistant form of IκBα lacking its N-terminal sequence impairs Th1 responses.40 The Th1 cell generation also requires c-Rel, which mainly functions by mediating induction of the Th1-polarizing cytokine in antigen-presenting cells.41 NF-κB1 p50, on the other hand, is important for Th2 responses and allergic airway inflammation, which appears to involve induction of the lineage transcription factor Gata3.42 Several NF-κB members have been shown to promote Th17 responses. Nfkb1 knockin mice that express p50 but not its precursor, the IκB-like molecule p105, display aberrant NF-κB activation and spontaneously develop colitis characterized by hyperproduction of Th17 cells.43 Although p105 deficiency has no T-cell intrinsic effect on Th17 cell differentiation, the aberrant activation of NF-κB renders innate immune cells hyperresponsive to TLR stimulation for production of IL-6, a major cytokine-promoting Th17 differentiation.43 A T-cell intrinsic role of NF-κB in regulating Th17 responses was initially indicated by a finding that mice with T-cell-specific IKKβ deletion have impaired T-cell activation and are refractory to the induction of a Th17-dependent autoimmune disease, experimental autoimmune encephalomyelitis (EAE).44 Subsequent work has definitively demonstrated a crucial role for c-Rel and RelA in mediating induction of the Th17 lineage transcription factor RORγt and the generation of Th17 cells.40,41 In CD4+ T cells, c-Rel also mediates TCR-stimulated expression of IL-21, a γc family cytokine important for the differentiation Th17 and Tfh cells.45 Consistently, the c-Rel-deficient mice have a defect in both Th17 and Tfh responses.45
Regulatory T (Treg) cells, generated along with thymocyte development or through CD4+ T-cell differentiation, are instrumental for controlling immune responses to prevent autoimmunity and chronic inflammation.46 Although NF-κB is known as a factor that promotes T-cell activation and effector T-cell differentiation, it is increasingly clear that the function of NF-κB in T-cell responses is paradoxical, since it is also involved in the generation of Treg cells. Mice deficient in various signaling components of the canonical NF-κB pathway, such as TAK1, IKK and the T-cell-specific TAK1/IKK-activating factors CARMA1 and Bcl10, have reduced production of Treg cells, whereas expression of a constitutive active IKKβ or deletion of the IKK-negative regulator CYLD promotes Treg development.47 The NF-κB member c-Rel is particularly important for mediating Treg development, and c-Rel acts by participating in the induction of Treg master transcription factor Foxp3.48,49 The canonical NF-κB signaling pathway is also required for maintaining the immunosuppressive function of Treg cells, since deletion of IKKβ or its upstream activator Ubc13 in Treg cells impairs the in vivo function of Treg cells and sensitizes Treg cells for acquiring Th1 and Th17 inflammatory effector functions under lymphopenic conditions.50
NF-κB in the regulation of NLRP3 inflammasome. The activation of NLRP3 inflammasome requires two signals, priming and activation. A prototypical example of priming is bacterial LPS binding to TLR4, leading to the activation of NF-κB signaling. In the nucleus, the active NF-κB promotes the transcription of NF-κB-dependent genes, such as NLRP3, Pro-IL-1β and Pro-IL-18, which are necessary for inflammasome activation. The second signal of inflammasome activation is provided by NLRP3 agonists that activates NLRP3 to trigger inflammasome assembly and mature IL-1β secretion. To date, mitochondrial damage is the most widely studied activating stimuli for NLRP3 pathway in terms of its connection to diverse inflammatory, metabolic and malignant diseases. NF-κB induces delayed accumulation of the autophagy receptor p62, which can specifically bind to mitochondrial poly-ubiquitin chains though E3 ubiquitin ligase Parkin, and thereby, negatively regulate inflammasome activation via mitophagic elimination.
NLRP3 inflammasome is currently the most extensively studied inflammasome, which is composed of NLRP3, ASC and pro-caspase 1, as well as an essential regulatory protein, NIMA-related kinase 7 (NEK7). Activation of the NLRP3 inflammasome usually requires both a priming signal (signal 1) and an activation signal (signal 2). A major role of the priming signal is to induce the transcriptional expression of NLRP3 and pro-IL, since most cell types have insufficient levels of NLRP3 for inflammasome activation and do not constitutively express pro-IL-1β.60,61 In addition, emerging evidence suggests that signal 1 may also prime NLRP3 via post-translational mechanisms, such as NLRP3 deubiquitination.62,63 Typical inducers of signal 1 include microbial components, such as TLR ligands, and cytokines like TNF-α and IL-1β, which are known to activate NF-κB, a transcriptional activator of both NLRP3 and pro-IL-1β genes. The second signal of inflammasome activation is triggered by various PAMPs and DAMPs, such as pore-forming toxins, viral RNAs, ATP and crystalline substances.60,64 These diverse stimuli are thought to activate NLRP3 via inducing different cellular events, including K+ efflux, Ca2+ signaling, mitochondrial and lysosomal damages that release substances such as reactive oxygen species, oxidized mitochondrial DNA and lysosomal proteases.61
NF-κB-targeted therapeutics in inflammatory diseases. NF-κB signaling plays a pathogenic role in various inflammatory diseases; therefore, there are many therapeutic strategies for inflammatory diseases aimed at blocking NF-κB activity. First, inhibition of IKK kinase activity. Drugs such as aspirin and salicylate have the ability to specifically inhibit IKK, thereby preventing phosphorylation of IκBα. Second, inhibition of protease activity. Drugs such as PS-341 and lactacystin specifically inhibit 26S proteasome complex, thereby preventing IκBα degradation. Third, inhibition of nuclear translocation. Drugs such as tacrolimus and IκBα super-repressor specifically prevent NF-κB subunits RelA, p50, c-Rel and other members from entering the nucleus. Finally, inhibition of DNA binding. Drugs such as glucocorticoids and PPAR agonists have the ability to prevent NF-κB subunits from binging with target genes, and therefore inhibit the transcription. 2ff7e9595c
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