Mechanisms of Persistent NF-κB Activity in the Bronchi of an Animal Model of Asthma

Bureau, Fabrice; Delhalle, Sylvie; Bonizzi, Giuseppina; Fiévez, Laurence; Dogné, Sophie; Kirschvink, Nathalie; Vanderplasschen, Alain; Merville, Marie‐Paule; Bours, Vincent; Lekeux, Pierre

doi:10.4049/jimmunol.165.10.5822

Cited by 115 publications

(83 citation statements)

References 45 publications

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“…However, these studies failed to consider the anatomical location of NF-B activation within the lung. NF-B activation has been demonstrated in lung tissue (30 -33), and specifically within airway epithelium, in animal models of allergic airway inflammation (6,7,34) and in patients with asthma (8 -13). Yet, conclusive evidence implicating the importance of NF-B activity within the airways in the etiology of allergic airways disease was lacking.…”

Section: Discussionmentioning

confidence: 99%

NF-κB Activation in Airways Modulates Allergic Inflammation but Not Hyperresponsiveness

Poynter¹,

Cloots²,

Woerkom³

et al. 2004

The Journal of Immunology

148

147

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Airways display robust NF-κB activation and represent targets for anti-inflammatory asthma therapies, but the functional importance of NF-κB activation in airway epithelium remains enigmatic. Therefore, transgenic mice were created in which NF-κB activation is repressed specifically in airways (CC10-IκBαSR mice). In response to inhaled Ag, transgenic mice demonstrated significantly ameliorated inflammation, reduced levels of chemokines, T cell cytokines, mucus cell metaplasia, and circulating IgE compared with littermate controls. Despite these findings, Ag-driven airways hyperresponsiveness was not attenuated in CC10-IκBαSR mice. This study clearly demonstrates that airway epithelial NF-κB activation orchestrates Ag-induced inflammation and subsequent adaptive immune responses, but does not contribute to airways hyperresponsiveness, the cardinal feature that underlies asthma.

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Section: Discussionmentioning

confidence: 99%

NF-κB Activation in Airways Modulates Allergic Inflammation but Not Hyperresponsiveness

Poynter¹,

Cloots²,

Woerkom³

et al. 2004

The Journal of Immunology

148

147

View full text Add to dashboard Cite

show abstract

“…However, in chronic inflammatory diseases, this negative regulating loop is overwhelmed by a positive one involving NF-B activation by TNF-␣ and IL-1␤ and NF-B-dependent expression of these two major proinflammatory cytokines. Indeed, chronic inflammatory diseases such as RA, asthma, or inflammatory bowel diseases are associated with persistent in situ NF-B activity (Bureau et al, 2000;Handel et al, 1995;Weber et al, 2000). Moreover, animal models in which the genes coding for the IB-␣ or A20 NF-B inhibitors have been inactivated present important and even fatal inflammatory reactions (Beg et al, 1995;Lee et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…The constitutive NF-B activity is required for cell survival (Bargou et al, 1997;Sovak et al, 1997;Wu et al, 1996), and NF-B activity protects many cell types from apoptotic death. In the context of the chronic inflammatory diseases, this activity is likely to maintain immune and inflammatory cell viability and to participate in the persistence of inflammation (Bureau et al, 2000(Bureau et al, , 2002.…”

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confidence: 99%

TNF-α Protects Human Primary Articular Chondrocytes from Nitric Oxide-Induced Apoptosis Via Nuclear Factor-κB

Relić

Bentires‐Alj

Ribbens

et al. 2002

Laboratory Investigation

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SUMMARY:TNF-␣ plays a key role in rheumatoid arthritis, but its effect on chondrocyte survival is still conflicting. In the present study, we tested how TNF-␣ influences chondrocyte survival in response to nitric oxide (NO)-related apoptotic signals, which are abundant during rheumatoid arthritis. Human primary articular chondrocytes or cartilage explants were pretreated with TNF-␣ for 24 hours and then treated with the proapoptotic NO donor sodium-nitro-prusside (SNP) for an additional 24 hours. TNF-␣ pretreatment markedly protected chondrocytes from SNP-induced cell death. Preincubation of chondrocytes with TNF-␣ inhibited both SNP-induced high-molecular weight DNA fragmentation and annexin V-FITC binding. Of interest, TNF-␣ induced persistent nuclear factor-B (NF-B)-DNA binding activity even in the presence of SNP, mirroring apoptosis protection effects. Both the TNF-␣ antiapoptotic effect and NF-B-DNA binding activity were significantly inhibited by NF-B inhibitors, Bay 11-7085, MG-132, and adenovirus-expressing mutated IB-␣. Phosphatidylinositol-3 kinase inhibitor LY 294002 also markedly inhibited the antiapoptotic effect of TNF-␣. In primary chondrocytes, TNF-␣ induced expression of the antiapoptotic protein Cox-2, which persisted in the presence of SNP, and a specific Cox-2 inhibitor significantly blocked the TNF-␣ protective effect. We therefore conclude that TNF-␣-mediated protection of chondrocytes from NO-induced apoptosis acts through NF-B and requires Cox-2 activity. (Lab Invest 2002, 82:1661-1672.C artilage loss associated with rheumatoid arthritis (RA) leads to irreversible joint dysfunction. Cartilage destruction results from metalloproteinasedependent matrix degradation and nitric oxide (NO)-induced chondrocyte apoptosis (Amin et al, 1999;Blanco et al, 1995;Lotz et al, 1999;Sakurai et al, 1995). Extracellular matrix modifications may also lead to chondrocyte apoptosis, as was shown in collagen II-deficient mice (Yang et al, 1997). Because chondrocytes are the only cells in the cartilage and the only matrix producers, their survival is the focus of many recent investigations (Blanco et al, 1998;Colnot et al, 2001;Hashimoto et al, 1998;Kim and Song, 1999).The proinflammatory cytokines TNF-␣ and IL-1␤ are indirectly responsible for cartilage degradation and chondrocyte death because they stimulate the synthesis and release of metalloproteinases and NO from monocytes-macrophages, synoviocytes, and chondrocytes. In vitro, however, conflicting results have been reported about the effect of proinflammatory cytokines on chondrocyte apoptosis (Aizawa et al, 2001;Blanco et al, 1995;Fischer et al, 2000;Kuhn et al, 2000;Lotz et al, 1999).Many TNF-␣ biologic activities are mediated by nuclear factor-B (NF-B). NF-B is maintained in the cytoplasm of most cell types under an inactive form associated with an inhibitor from the IB family, such as the ubiquitous IB-␣ protein. After cellular stimulation with TNF-␣, NF-B nuclear activity is rapidly induced as a consequence of IKK kinase activation and IB-␣ phosphory...

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“…2 Activity of NF-kB is increased in bronchial cells of RAO-affected horses and is highly correlated to the percentage of neutrophils present in the bronchi. 5,6 Selective blockage of NF-kB activity results in marked attenuation of allergic lung inflammation in antigen-sensitized mice. 9 On the basis of the results of the present study, whereby neutrophil chemoattractant activity in BALF was assessed with the MTT assay and found to be higher in RAO-affected horses compared with normal horses, this assay may be useful for monitoring the response to therapy of RAO-affected horses in future studies, regardless of the underlying chemoattractant.…”

Section: Discussionmentioning

confidence: 99%

Rapid, Multiwell Colorimetric Assay for Measuring Neutrophil Chemoattractant Activity in Bronchoalveolar Lavage Fluid of Horses with Recurrent Airway Obstruction

et al. 2006

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Abstract. The criteria used to diagnose recurrent airway obstruction (RAO) in affected horses include demonstration of reversible lower airway obstruction and greater than 25% neutrophils in bronchoalveolar lavage fluid (BALF). Additional objective laboratory tests are needed to improve diagnostic accuracy and to monitor response to treatment. The goal of this study was to determine if neutrophil chemoattractant activity of BALF could be measured by using a previously described, rapid, multiwell colorimetric assay for chemotaxis. In this assay, neutrophils that have migrated through a membrane filter are collected into the bottom well of a disposable chemotaxis-cell migration chamber. The number of viable cells collected in the bottom well is quantified by measurement of the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenol tetrazolium bromide (MTT), which is reduced by dehydrogenase in mitochondria of live cells. The number of migrating cells corresponds to the amount of MTT reduced, which is measured with an enzyme-linked immunosorbent assay plate reader. Fourteen adult horses were enrolled in this study, 7 of which had owner histories consistent with RAO. Each horse was sedated, a bronchoalveolar lavage tube was passed, and saline was infused and immediately aspirated. An aliquot of BALF was used for differential cell count, and BALF supernatant was harvested to assess neutrophil chemoattractant activity. Normal control horses and RAOaffected horses were distinguished according to clinical signs and percent neutrophils in BALF. Neutrophil chemoattractant activity of BALF was significantly greater in RAO-affected horses (P 5 0.001) compared with control horses. This assay may be useful in future studies for monitoring response to therapy in RAOaffected horses.

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Mechanisms of Persistent NF-κB Activity in the Bronchi of an Animal Model of Asthma

Cited by 115 publications

References 45 publications

NF-κB Activation in Airways Modulates Allergic Inflammation but Not Hyperresponsiveness

NF-κB Activation in Airways Modulates Allergic Inflammation but Not Hyperresponsiveness

TNF-α Protects Human Primary Articular Chondrocytes from Nitric Oxide-Induced Apoptosis Via Nuclear Factor-κB

Rapid, Multiwell Colorimetric Assay for Measuring Neutrophil Chemoattractant Activity in Bronchoalveolar Lavage Fluid of Horses with Recurrent Airway Obstruction

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