IκB kinase–driven nuclear factor-κB activation in patients with asthma and chronic obstructive pulmonary disease

Gagliardo, Rosalia; Chanez, Pascal; Profita, Mirella; Bonanno, Anna; Albano, Giusy Daniela; Montalbano, Angela Marina; Pompeo, Flora; Gagliardo, Cesare; Merendino, Anna Maria; Gjomarkaj, Mark

doi:10.1016/j.jaci.2011.03.045

Cited by 48 publications

(39 citation statements)

References 48 publications

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“…In support of these findings, the present study demonstrates similar proinflammatory effects of CA-IKKa in primary tracheal epithelial cells. In support of the contributions of both IKKa and IKKb to pulmonary inflammation, a recent study showed the increased activity of IKKb and IKKa in both healthy smokers and patients with chronic obstructive pulmonary disease (51). The siRNA-mediated knockdown of IKKa in peripheral blood mononuclear cells isolated from these patients resulted in decreases in IL-8 production, illustrating a proinflammatory role for IKKa.…”

Section: Discussionmentioning

confidence: 88%

Cooperation between Classical and Alternative NF-κB Pathways Regulates Proinflammatory Responses in Epithelial Cells

Tully

Nolin²,

Guala³

et al. 2012

Am J Respir Cell Mol Biol

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The transcription factor NF-kB has been causally linked to inflammatory lung diseases. Recent studies have unraveled the complexity of NF-kB activation by identifying two parallel activation pathways: the classical NF-kB pathway, which is controlled by IkB kinase complex-b (IKKb) and RelA/p50, and the alternative pathway, which is controlled by IKKa and RelB/p52. The alternative pathway regulates adaptive immune responses and lymphoid development, yet its role in the regulation of innate immune responses remains largely unknown. In this study, we determined the relevance of the alternative NF-kB pathway in proinflammatory responses in lung epithelial cells. The exposure of C10 murine alveolar lung epithelial cells to diverse stimuli, or primary murine tracheal epithelial cells to LPS, resulted in the activation of both NF-kB pathways, based on the nuclear translocation of RelA, p50, RelB, and p52. Increases in the nuclear content of RelA occurred rapidly, but transiently, whereas increases in nuclear RelB content were protracted. The small interfering (si) RNAmediated knockdown of IKKa, RelA, or RelB resulted in decreases of multiple LPS-induced proinflammatory cytokines. Surprisingly, the siRNA ablation of IKKa or RelB led to marked increases in the production of IL-6 in response to LPS. The simultaneous expression of constitutively active (CA)-IKKa and CA-IKKb caused synergistic increases in proinflammatory mediators. Lastly, the disruption of the IKK signalsome inhibited the activation of both NF-kB pathways. These results demonstrate that the coordinated activation of both NF-kB pathways regulates the magnitude and nature of proinflammatory responses in lung epithelial cells.Keywords: lung; IkB kinase-b; IkB kinase-a; RelA; RelB NF-kB is a transcription factor that plays a cardinal role in multiple cellular processes, including survival, proliferation, and inflammation. In unstimulated cells, NF-kB dimers RelA and p50 are sequestered in the cytosol by the inhibitor of kB (IkBa). The IkB kinase complex (IKK) consists of two catalytic subunits, IKKb and IKKa, and the regulatory protein, IKKg (also known as NF-kB essential modulator). Upon ligation by a variety of stimuli such as TNF-a or Toll-like receptor agonists, IKKb is phosphorylated and in turn phosphorylates IkBa, leading to its subsequent ubiquitination and degradation by the 26S proteasome (1, 2). The processing of IkBa promotes the nuclear translocation of RelA/p50, leading to the transcriptional activation of NF-kB-dependent genes. NF-kB activates the transcription of many proinflammatory cytokine and chemokine genes that initiate and propagate innate immune responses (1, 2).The airway epithelium, classically regarded as the first line of defense against inhaled agents, toxic factors, and physical trauma, is now recognized as a key component of the innate immune system, and plays an active role in the orchestration of acute inflammatory and adaptive immune responses (3, 4). Upon stimulation, epithelial cells secrete proinflammatory mediators such as...

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Section: Discussionmentioning

confidence: 88%

Cooperation between Classical and Alternative NF-κB Pathways Regulates Proinflammatory Responses in Epithelial Cells

Tully

Nolin²,

Guala³

et al. 2012

Am J Respir Cell Mol Biol

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“…There is also evidence for NF-κ B activation in bronchial epithelial and sputum cells of patients with stable asthma (Hart et al, 1998), in the peripheral blood mononuclear cells of patients with severe uncontrolled asthma (Gagliardo et al, 2003(Gagliardo et al, , 2011 and in the bronchial and bronchiolar epithelium of patients who died during an asthmatic exacerbation . Furthermore rhinovirus infection of asthmatic patients in vivo is associated with enhanced NF-κ B p65 nuclear expression in bronchial epithelial cell, increased NF-κ B p65 DNA binding in lung tissue and elevated levels of NF-κ B-regulated infl ammatory mediators (Bartlett et al, 2012).…”

Section: Role Of the Transcription Factor Nf-κ B In The Pathogenesis mentioning

confidence: 99%

Role of Transcription Factors in the Pathogenesis of Asthma and COPD

Caramori¹,

Casolari²,

Adcock

2013

Cell Communication & Adhesion

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Infl ammation is a central feature of asthma and chronic obstructive pulmonary disease (COPD). Despite recent advances in the knowledge of the pathogenesis of asthma and COPD, much more research on the molecular mechanisms of asthma and COPD are needed to aid the logical development of new therapies for these common and important diseases, particularly in COPD where no effective treatments currently exist. In the future the role of the activation/repression of different transcription factors and the genetic regulation of their expression in asthma and COPD may be an increasingly important aspect of research, as this may be one of the critical mechanisms regulating the expression of different clinical phenotypes and their responsiveness to therapy, particularly to anti-infl ammatory drugs.

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“…Excessive activation of NF-κB can cause reduced or absent responsiveness to glucocorticoids in asthma, since NF-κB binds the glucocorticoid receptor, preventing its interaction with the glucocorticoid response element and other transcription factors. PBMCs from uncontrolled severe adult asthmatics showed higher levels of NF-κB p65 protein expression, IκBα phosphorylation and IKKβ kinase activity than normal individuals, despite long-term inhaled and oral glucocorticosteroid treatment [9,23]. A similar state of overexpression and activation of NF-κB p65 subunit protein in PBMCs and induced sputum cells has been shown in children with moderate to severe asthma [13,32].…”

Section: Foxp3mentioning

confidence: 78%

“…IKKβ activation seems to be specific for asthma, since increased IKKα activity was found in patients with COPD and healthy smokers compared with asthmatic patients or controls [23]. The different profile in the upstream regulation of the IKK-driven NF-κB system in asthmatic and in COPD patients may explain, at least in part, the different pro-inflammatory and pharmacological responses in asthmatic versus COPD patients.…”

Section: Airway Inflammation and Remodellingmentioning

confidence: 98%

“…As a further support to the assessment of systemic inflammation to manage asthmatics, it has been shown that IκB kinase (IKK), a complex tightly regulating NF-κB activation, and in particular IKKβ activity, was higher in PBMCs in asthmatic patients than in controls [23]. IKKβ activation seems to be specific for asthma, since increased IKKα activity was found in patients with COPD and healthy smokers compared with asthmatic patients or controls [23].…”

Section: Airway Inflammation and Remodellingmentioning

confidence: 99%

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Advances in asthma pathophysiology: stepping forward from the Maurizio Vignola experience

et al. 2015

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Maurizio Vignola was a superb and innovative researcher, who wrote seminal papers on the biology of airway epithelium in asthma. Inflammation and remodelling were the main topics of his research, mostly conducted in biopsy specimens from patients with asthma of variable severity, encompassing the entire spectrum of the disease from mild to severe asthma. His observations contributed to define the biology of asthma as we know it today, and opened the way to the personalised treatment of asthma. His group has successfully continued to investigate the biology and clinical aspects of bronchial asthma, with major interest in the clinical use of biomarkers to monitor disease activity, and in the development of new therapeutic perspectives. This review summarises the latest work on these topics proudly conducted by Maurizio's closest collaborators. The results indicate significant progress in our understanding of asthma in the last 10 years, in particular increased knowledge of the complex interaction between inflammatory and remodelling pathways, improved recognition of biological and clinical asthma phenotypes, and development of new treatment strategies, especially for patients with severe corticosteroid-resistant asthma. @ERSpublications Biomarkers may help to define disease phenotypes and new treatment strategies for asthma

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IκB kinase–driven nuclear factor-κB activation in patients with asthma and chronic obstructive pulmonary disease

Cited by 48 publications

References 48 publications

Cooperation between Classical and Alternative NF-κB Pathways Regulates Proinflammatory Responses in Epithelial Cells

Cooperation between Classical and Alternative NF-κB Pathways Regulates Proinflammatory Responses in Epithelial Cells

Role of Transcription Factors in the Pathogenesis of Asthma and COPD

Advances in asthma pathophysiology: stepping forward from the Maurizio Vignola experience

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