Nuclear localization of the transcriptional activator NF-κB (nuclear factor κB) is controlled in mammalian cells by three isoforms of NF-κB inhibitor protein: IκBα, -β, and -ɛ Based on simplifying reductions of the IκB–NF-κB signaling module in knockout cell lines, we present a computational model that describes the temporal control of NF-κB activation by the coordinated degradation and synthesis of IκB proteins The model demonstrates that IκBα is responsible for strong negative feedback that allows for a fast turn-off of the NF-κB response, whereas IκBβ and -ɛ function to reduce the system's oscillatory potential and stabilize NF-κB responses during longer stimulations Bimodal signal-processing characteristics with respect to stimulus duration are revealed by the model and are shown to generate specificity in gene expression

https://science.sciencemag.org/content/sci/298/5596/1241.full.pdf

The IκB-NF-κB Signaling Module: Temporal Control and Selective Gene Activation

Atherosclerosis is a chronic disease of the arterial wall where both innate and adaptive immunoinflammatory mechanisms are involved. Inflammation is central at all stages of atherosclerosis. It is implicated in the formation of early fatty streaks, when the endothelium is activated and expresses chemokines and adhesion molecules leading to monocyte/lymphocyte recruitment and infiltration into the subendothelium. It also acts at the onset of adverse clinical vascular events, when activated cells within the plaque secrete matrix proteases that degrade extracellular matrix proteins and weaken the fibrous cap, leading to rupture and thrombus formation. Cells involved in the atherosclerotic process secrete and are activated by soluble factors, known as cytokines. Important recent advances in the comprehension of the mechanisms of atherosclerosis provided evidence that the immunoinflammatory response in atherosclerosis is modulated by regulatory pathways, in which the two anti-inflammatory cytokines interleukin-10 and transforming growth factor-beta play a critical role. The purpose of this review is to bring together the current information concerning the role of cytokines in the development, progression, and complications of atherosclerosis. Specific emphasis is placed on the contribution of pro- and anti-inflammatory cytokines to pathogenic (innate and adaptive) and regulatory immunity in the context of atherosclerosis. Based on our current knowledge of the role of cytokines in atherosclerosis, we propose some novel therapeutic strategies to combat this disease. In addition, we discuss the potential of circulating cytokine levels as biomarkers of coronary artery disease.

/pdf/cytokines-in-atherosclerosis-pathogenic-and-regulatory-k5l4m0ggqp.pdf

Cytokines in atherosclerosis: pathogenic and regulatory pathways.

The last decade has witnessed a major reassessment of our perceptions about the acute coronary syndromes. Today, we recognize that thrombosis underlies most acute complications of atherosclerosis, notably unstable angina and acute myocardial infarction. A consensus has emerged that inflammation plays a decisive role in the pathophysiology of these acute thrombotic events (Figure 1). Knowledge of the underlying mechanisms has increased substantially since this topic was last reviewed in these pages 6 years ago. The present article provides an update of this rapidly moving field. 



Figure 1. Initiation, progression, and complication of human coronary atherosclerotic plaque. Top, Longitudinal section of artery depicting “timeline” of human atherogenesis from normal artery (1) to atheroma that caused clinical manifestations by thrombosis or stenosis (5, 6, 7). Bottom, Cross sections of artery during various stages of atheroma evolution. 1, Normal artery. Note that in human arteries, the intimal layer is much better developed than in most other species. The intima of human arteries contains resident smooth muscle cells often as early as first year of life. 2, Lesion initiation occurs when endothelial cells, activated by risk factors such as hyperlipoproteinemia, express adhesion and chemoattractant molecules that recruit inflammatory leukocytes such as monocytes and T lymphocytes. Extracellular lipid begins to accumulate in intima at this stage. 3, Evolution to fibrofatty stage. Monocytes recruited to artery wall become macrophages and express scavenger receptors that bind modified lipoproteins. Macrophages become lipid-laden foam cells by engulfing modified lipoproteins. Leukocytes and resident vascular wall cells can secrete inflammatory cytokines and growth factors that amplify leukocyte recruitment and cause smooth muscle cell migration and proliferation. 4, As lesion progresses, inflammatory mediators cause expression of tissue factor, a potent procoagulant, and of matrix-degrading proteinases that weaken fibrous cap of plaque. 5, If fibrous cap ruptures at point of weakening, coagulation factors …

Current Concepts of the Pathogenesis of the Acute Coronary Syndromes

Accumulating evidence indicates that reactive oxygen species (ROS) play major roles in the initiation and progression of cardiovascular dysfunction associated with diseases such as hyperlipidemia, diabetes mellitus, hypertension, ischemic heart disease, and chronic heart failure. ROS produced by migrating inflammatory cells as well as vascular cells (endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts) have distinct functional effects on each cell type. These include cell growth, apoptosis, migration, inflammatory gene expression, and matrix regulation. ROS, by regulating vascular cell function, can play a central role in normal vascular physiology, and can contribute substantially to the development of vascular disease.

Reactive Oxygen Species in the Vasculature. Molecular and Cellular Mechanisms

https://www.gastrojournal.org/article/S0016-5085(02)21221-4/pdf

Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein

Interleukin-6 (IL-6) is a multifunctional cytokine expressed by angiotensin II (Ang II)-stimulated vascular smooth muscle cells (VSMCs) that functions as an autocrine growth factor. In this study, we analyze the mechanism for Ang II-inducible IL-6 expression in quiescent rat VSMCs. Stimulation with the Ang II agonist Sar1 Ang II (100 nmol/L) induced transcriptional expression of IL-6 mRNA transcripts of 1.8 and 2.4 kb. In transient transfection assays of IL-6 promoter/luciferase reporter plasmids, Sar1 Ang II treatment induced IL-6 transcription in a manner completely dependent on the nuclear factor-kappaB (NF-kappaB) motif. Sar1 Ang II induced cytoplasmic-to-nuclear translocation of the NF-kappaB subunits Rel A and NF-kappaB1 with parallel changes in DNA-binding activity in a biphasic manner, which produced an early peak at 15 minutes followed by a nadir 1 to 6 hours later and a later peak at 24 hours. The early phase of NF-kappaB translocation was dependent on weak simultaneous proteolysis of the IkappaBalpha and beta inhibitors, whereas later translocation was associated with enhanced processing of the p105 precursor into the mature 50-kDa NF-kappaB1 form. Pretreatment with a potent inhibitor of IkappaBalpha proteolysis, TPCK, completely blocked Sar1 Ang IIAng II-induced NF-kappaB activation and induction of endogenous IL-6 gene expression, which indicated the essential role of NF-kappaB in mediating IL-6 expression. We conclude that Ang II is a pleiotropic regulator of the NF-kappaB transcription factor family and may be responsible for activating the expression of cytokine gene networks in VSMCs.

/pdf/angiotensin-ii-induces-interleukin-6-transcription-in-2yog9vj5an.pdf

Angiotensin II induces interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-κB transcription factors

Tumor Necrosis Factor-α-inducible IκBα Proteolysis Mediated by Cytosolic m-Calpain A MECHANISM PARALLEL TO THE UBIQUITIN-PROTEASOME PATHWAY FOR NUCLEAR FACTOR-κB ACTIVATION

Mechanism for Biphasic Rel A· NF-κB1 Nuclear Translocation in Tumor Necrosis Factor α-stimulated Hepatocytes

The enveloped negative-sense RNA virus respiratory syncytial virus (RSV) is the major cause of bronchiolitis and pneumonia in infants and young children (20). In addition to producing persistent airway hyperreactivity in previously healthy children, RSV infection is a major cause of morbidity in children with preexisting pulmonary or heart disease (18, 28, 48). RSV replicates primarily in the respiratory epithelial cell. The infected airway epithelial cell is an important initiator in the response to RSV infection, by synthesizing and secreting potent cytokines that are involved in the immune and inflammatory responses in the airway mucosa (16, 41).

Recent studies have demonstrated that the cytokines interleukin-1 (IL-1), IL-6, IL-8, IL-11, RANTES, macrophage inflammatory protein-1α, monocyte chemotactic protein-1, granulocyte/macrophage stimulatory factor, tumor necrosis factor alpha (TNF-α), and the soluble TNF receptor are produced by RSV-infected respiratory epithelial cells and may play important roles in the development of inflammation in vivo (2, 4, 16, 17, 30, 38). Of particular relevance to mononuclear inflammation, IL-8 gene expression is activated at the level of transcription through the effects of RSV-inducible transcription factors nuclear factor-κB (NF-κB) and NF-IL6 (4, 13, 17, 25, 29). From these studies, NF-κB emerges as the primary activator of IL-8 transcription whose binding is absolutely required for inducible expression (5, 13). Indeed, NF-κB translocation appears to be essential for activity not only of IL-8 but also of a genetic network including the cytokines IL-1, IL-6, and IL-11 in the RSV-infected epithelium (4). NF-κB constitutes a family of cytokine-inducible transcription factors that include the potent RelA (p65) transactivator, as well as the RelB, c-Rel, NF-κB1 (p50), and NF-κB2 (p52) (the last two being encoded by the proteolytically processed precursors p105 and p100, respectively [40]) subunits. Inducible NF-κB subunits interact with cytoplasmic inhibitors, collectively known as IκBs, through motifs contained within a conserved NH2-terminal Rel homology domain (3). IκB subunits, responsible for cytoplasmic retention and inactivation of NF-κB DNA-binding activity, consist predominantly of four isoforms, IκBα, IκBβ, IκBγ, and the NF-κB1 precursor, p105, that are expressed and regulated in a cell specific fashion (21, 23, 44).

NF-κB-inducing signals control its cytoplasmic-nuclear abundance by a mechanism involving proteolytic degradation of the IκB inhibitor. Once liberated, free cytoplasmic NF-κB passes through the nuclear pore complex and enters the nucleus (translocates), to bind and activate target genes. Stimulation of cells with the prototypical activator TNF-α results in rapid serine phosphorylation of the IκBα NH2 terminus (6, 45), an event coupled to the rapid polyubiquitination and proteolysis of phospho-IκB (IκBαP) through the 26S proteasome (1, 10). The role of the 26S proteasome has been implicated by the ability of the proteasome-specific calpain inhibitor I, Z-LLF-CHO, or MG-132 to block IκB proteolysis in TNF-α-stimulated cells (1, 5, 10, 12, 37, 46).

Although we have shown that pRSV infection increases the nuclear abundance of NF-κB (RelA) in A549 cells, its mechanism of activation is unexplored. Therefore, we systematically investigated the mechanism and kinetics of NF-κB activation in pRSV-infected airway epithelial cells in comparison to those of TNF-α. We show herein that in contrast to the rapid activation of RelA produced by TNF-α, pRSV infection produces a gradual increase in RelA binding peaking at 24 h. For both activators TNF-α and pRSV, IκBα and IκBβ proteolysis occurred in parallel with the increases in RelA DNA-binding activity. Although specific proteasome inhibitors significantly block 26S protease activity and IκBα proteolysis by TNF-α, they do not completely prevent IκBα proteolysis by pRSV infection. These data indicate that a major aspect of IκBα proteolysis occurs via a proteasome-independent mechanism in virus-infected epithelium.

The Major Component of IκBα Proteolysis Occurs Independently of the Proteasome Pathway in Respiratory Syncytial Virus-Infected Pulmonary Epithelial Cells

The vasopressor angiotensin II (AII) activates transcriptional expression of its precursor, angiotensinogen. This biological “positive feedback loop” occurs through an angiotensin receptor-coupled pathway that activates a multihormone-responsive enhancer of the angiotensinogen promoter, termed the acute-phase response element (APRE). Previously, we showed that the APRE is a cytokine [tumor necrosis factor-α (TNFα)]- inducible enhancer by binding the heterodimeric nuclear factor-κB (NF-κB) complex Rel A•NF-κB1. Here, we compare the mechanism for NF-κB activation by the AII agonist, Sar1 AII, with TNFα in HepG2 hepatocytes. Although Sar1 AII and TNFα both rapidly activate APRE-driven transcription within 3 h of treatment, the pattern of inducible NF-κB binding activity in electrophoretic mobility shift assay is distinct. In contrast to the TNFα mechanism, which strongly induces Rel A•NF-κB1 binding, Sar1 AII selectively activates a heterogenous pattern of NF-κB1 binding. Using a two-step microaffinity DNA b...

/pdf/angiotensin-ii-induces-nuclear-factor-nf-kb1-isoforms-to-2kxaq9siy1.pdf

Angiotensin II Induces Nuclear Factor (NF)-κB1 Isoforms to Bind the Angiotensinogen Gene Acute-Phase Response Element: A Stimulus-Specific Pathway for NF-κB Activation

Youqi Han

Papers

Angiotensin II induces interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-κB transcription factors

Tumor Necrosis Factor-α-inducible IκBα Proteolysis Mediated by Cytosolic m-Calpain A MECHANISM PARALLEL TO THE UBIQUITIN-PROTEASOME PATHWAY FOR NUCLEAR FACTOR-κB ACTIVATION

Mechanism for Biphasic Rel A· NF-κB1 Nuclear Translocation in Tumor Necrosis Factor α-stimulated Hepatocytes

The Major Component of IκBα Proteolysis Occurs Independently of the Proteasome Pathway in Respiratory Syncytial Virus-Infected Pulmonary Epithelial Cells

Angiotensin II Induces Nuclear Factor (NF)-κB1 Isoforms to Bind the Angiotensinogen Gene Acute-Phase Response Element: A Stimulus-Specific Pathway for NF-κB Activation