Chest
Impact of Basic Research on Tomorrow's MedicineThe Role of Nuclear Factor-κ B in Pulmonary Diseases
Section snippets
Molecular Biology of NF-κB
As with other transcription factors, NF-κB binds to DNA in the promoter regions of target genes as a dimer usually composed of two Rel family proteins, p50 (also called NF-κB1) and RelA (also called p65). In the NF-κB heterodimer, both subunits contact DNA, but only RelA contains a transactivation domain that activates transcription by direct interaction with the basal transcription apparatus.4 In quiescent cells, NF-κB is sequestered in the cytoplasm by its interaction with a member of the
NF-κB Activation Pathway
Although a wide variety of stimuli can activate NF-κB, among the most potent inducers are Gram-negative endotoxin or lipopolysaccharide (LPS), TNF-α, and IL-1β. A simplified version of the key signaling events that link LPS, TNF-α, and IL-1β through their cell surface receptors to NF-κB activation is shown in Figure 1 . Mercurio and Manning8 have recently written a concise and scholarly review that deciphers much of the most current information about activation of NF-κB. As indicated above,
Role of NF-κB in the Pathogenesis of Acute Lung Injury and SIRS
Although many animal and cell studies have implicated the NF-κB pathway in the pathogenesis of acute lung injury (ALI) and SIRS, only a few clinical studies have been published. The hypothesis is that in ALI and SIRS, the triad of endotoxin (LPS), TNFα, and IL-1β results in activation of NF-κB in the lung and other organs, which leads to cytokine and chemokine gene expression and neutrophil-associated organ dysfunction, clinically recognized as multiple organ dysfunction syndrome. In this
Role of NF-κB in the Pathogenesis of Asthma
Asthma is an inflammatory disease of the airways that is associated with reversible bronchial hyperreactivity. The pathogenesis of asthma seems to involve expression of a broad array of inflammatory proteins, including cytokines, enzymes, and adhesion molecules, that are regulated by NF-κB. Three lines of evidence suggest a central role of NF-κB in the pathogenesis of asthma: (1) activated NF-κB has been identified in key locations in the airways of asthmatic patients; (2) agents such as
Role of NF-κB in the Pathogenesis of Mineral Dust Disease
Two groups have intensely investigated the role of NF-κB in asbestosis using in vitro cell lines and animal models.31, 3233, 3435, 36 The hypothesis is that iron present in asbestos fibers induces cellular redox changes by facilitating production of intracellular reactive oxygen species through Fenton-like chemistry, resulting in activation of NF-κB. Reactive oxygen species are potent stimuli, which activate at least two transcription factors, NF-κB and activator protein-1, through a mechanism
CF
CF is a chronic inflammatory airway disease that is caused by mutations of the CFTR gene. Lung disease in CF presumably results from chronic airway inflammation related to increased viscosity of respiratory secretions and colonization with Pseudomonas and other bacterial species. Pseudomonas aeruginosa apparently leads to activation of NF-κB and could have a role in overproduction of mucin through activation of MUC2 mucin transcription.42 Although little in vivo data exist, increased activation
Summary
NF-κB has been shown to regulate production of acute inflammatory mediators in a variety of cell and animal models developed to elucidate the pathobiology of lung diseases. In addition, there are some emerging clinical data relating NF-κB activation to the pathogenesis of ARDS, SIRS, and asthma. In ARDS and SIRS, NF-κB activation in alveolar macrophages and other lung cell types very likely modulates neutrophilic alveolitis and lung injury. In asthma, NF-κB activation in airway epithelial cells
References (45)
- et al.
Multiple signals converging on NF-κB
Curr Opin Cell Biol
(1999) - et al.
Constitutive NF-κB levels in human alveolar macrophages from normal volunteers
Cytokine
(1998) - et al.
Use of genetically altered mice to investigate the role of NF-κB activation and cytokine gene expression in sepsis induced ARDS
Chest
(1999) - et al.
The allergen Der p1 induced NF-κB activation through interference with IκB alpha function in asthmatic bronchial epithelial cells
Biochem Biophys Res Commun
(1997) - et al.
Ozone induction of cytokine-induced neutrophil chemoattractant (CINC) and nuclear factor-kappa b in rat lung: inhibition by corticosteroids
FEBS Lett
(1996) - et al.
Rhinovirus infection induces expression of its own receptor intercellular adhesion molecule 1 (ICAM-1) via increased NF-kappa B-mediated transcription
J Biol Chem
(1999) - et al.
The role of oxidant stress in rhinovirus induced elaboration of IL-8 by respiratory epithelial cells
Free Radic Biol Med
(1999) - et al.
Transcriptional induction of multiple cytokine by human respiratory syncytial virus requires activation of NF-κB and is inhibited by sodium salicylate and aspirin
Virology
(1997) - et al.
Asbestos induces inflammatory cytokines in the lung through redox sensitive transcription factors
Toxicol Lett
(1998) - et al.
Intracellular oxidation/reduction status in the regulation of transcription factors NF-κB and AP-1
Toxicol Lett
(1999)
The role of nuclear factor kappa B in cytokine gene regulation
Am J Respir Cell Mol Biol
Nuclear factor kappa B: a pivotal role in the systemic response syndrome and new target for therapy
Intensive Care Med
Structure, regulation and function of NF-κB
Ann Rev Cell Biol
The p65 subunit is responsible for the strong transcription activating potential of NF-κB
EMBO J
Cytokine-inducible expression in endothelial cells of an IκB-α-like gene is regulated by NF-κB
EMBO J
Promoter analysis of the gene encoding the IκB-α/MAD3 inhibitor of NF-κB: positive regulation by members of the rel/NF-κB family
EMBO J
Role of unphosphorylated, newly synthesized IkBβ in persistent activation of NF-κB
Mol Cell Biol
Nuclear factor kappa B is activated in alveolar macrophages from patients with acute respiratory distress syndrome
Crit Care Med
Essential role of alveolar macrophage in intrapulmonary activation of NF-κB
Am J Respir Cell Mol Biol
Serial measurements of BAL cell nuclear factor kappa B (NF-κB) activation in patients with SIRS and/or ARDS [abstract]
Am J Respir Crit Care Med
Role of NFκB in the mortality of sepsis
J Clin Invest
Cytokines, chemokines, RANTES, and eotaxin
Allergy Asthma Proc
Cited by (311)
Recent trends of NFκB decoy oligodeoxynucleotide-based nanotherapeutics in lung diseases
2021, Journal of Controlled ReleaseNuclear factor-kappa B and its role in inflammatory lung disease
2021, Chemico-Biological InteractionsVitamin D Clinical Pharmacology: Relevance to COVID-19 Pathogenesis
2021, Journal of the National Medical AssociationInhibition of porcine reproductive and respiratory syndrome virus by PKC inhibitor dequalinium chloride in vitro
2020, Veterinary Microbiology
Supported by The Cystic Fibrosis Foundation, the US Department of Veterans Affairs, and grants HL 61419 and HL 07123 from the National Heart, Lung, and Blood Institute, National Institutes of Health.