Cell autonomous expression of inflammatory genes in biologically aged fibroblasts associated with elevated NF-kappaB activity

Kriete, Andres; Mayo, Kelli L.; Yalamanchili, Nirupama; Beggs, William; Bender, Patrick K.; Kari, Csaba; Rodeck, Ulrich

doi:10.1186/1742-4933-5-5

Cited by 52 publications

(53 citation statements)

References 49 publications

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“…The results of our study suggest that cellular senescence in the lungs not only limits cell proliferation but promotes inflammation, corroborating the results of previous studies that showed increased production of proinflammatory cytokines by different types of cells, such as fibroblasts and endothelial cells, that underwent senescence in vitro [24,25,26]. The overproduction of IL-6, IL-8 and TNF-α by senescent alveolar epithelial cells observed in this study may result in the establishment of a positive feedback loop, since TNF-α, for example, activates NF-ĸB signaling in alveolar epithelial cells and thereby stimulates them to produce proinflammatory cytokines [27,28].…”

Section: Discussionsupporting

confidence: 80%

“…The second limitation is that we do not know whether other types of pulmonary cells, such as endothelial cells and fibroblasts, also exhibit a proinflammatory phenotype when they become senescent. In this context, recent studies have shown constitutive activation of inflammatory pathways in senescent human umbilical vein endothelial cells [25] and senescent skin fibroblasts [26]. In the present study, we also found that senescent HDMECs produced greater amounts of IL-6, IL-8 and TNF-α than presenescent HDMECs.…”

Section: Discussionsupporting

confidence: 76%

“…For example, constitutive activation and nuclear translocation of NF-ĸB has been observed both in fibroblasts subjected to replicative senescence in vitro and in samples of skin, brain, heart, vasculature, lymphoid and lung tissue from aged animals [26,32,33,34,35,36]. These findings, together with our own, illustrate a critical role of NF-ĸB that may account for chronic inflammation during normal aging and in age-related diseases [34,35].…”

Section: Discussionmentioning

confidence: 99%

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Alveolar Cell Senescence Exacerbates Pulmonary Inflammation in Patients with Chronic Obstructive Pulmonary Disease

2009

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Background: Alveolar cell senescence is accelerated in patients with chronic obstructive pulmonary disease (COPD). Objectives: We tested the hypothesis that alveolar cell senescence contributes to the chronic inflammation that affects the lungs of COPD patients. Methods: We exposed alveolar type II-like epithelial (A549) cells to a G-quadruplex-interacting telomerase inhibitor in vitro to induce cellular senescence and analyzed the production of proinflammatory cytokines and the activation of NF-ĸB. Human dermal microvascular endothelial cells (HDMECs) were serially passaged to induce replicative senescence. We also immunostained human lung tissue sections obtained from COPD patients, asymptomatic smokers and asymptomatic nonsmokers and examined correlations between type II cell senescence and inflammation. Results: Senescent A549 cells and HDMECs, whether stimulated with lipopolysaccharide or not, produced greater amounts of IL-6, IL-8 and TNF-α, which paralleled NF-ĸB activation, than did presenescent cells. There were positive correlations between the percentages of senescent type II cells that expressed p16^INK4a and the percentages of type II cells that expressed phosphorylated NF-ĸB. The lung tissue of the COPD patients contained higher percentages of proinflammatory senescent type II cells that co-expressed p16^INK4a and phosphorylated NF-ĸB than the tissue from asymptomatic smokers and asymptomatic nonsmokers. Higher percentages of p16^INK4a-positive senescent type II cells than of p16^INK4a-negative presenescent type II cells were positive for phosphorylated NF-ĸB. Conclusions: Senescence of alveolar epithelial cells is associated with functional alterations of the cells to a proinflammatory phenotype and may contribute to the pathogenesis of COPD.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

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Alveolar Cell Senescence Exacerbates Pulmonary Inflammation in Patients with Chronic Obstructive Pulmonary Disease

2009

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“…In contrast, the percentage of EGFP + cells was 35% lower in the spleens of Ercc1 -/-NF-κB EGFP mice than in those of WT NF-κB EGFP littermates, indicating that NF-κB activation is not exclusively driven by inflammation. These data support earlier reports (22,23) that there is increased NF-κB activation with mammalian aging and extend this to include a murine model of XFE progeroid syndrome, which is driven by a DNA repair defect.…”

Section: Figuresupporting

confidence: 79%

NF-κB inhibition delays DNA damage–induced senescence and aging in mice

et al. 2012

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The accumulation of cellular damage, including DNA damage, is thought to contribute to aging-related degenerative changes, but how damage drives aging is unknown. XFE progeroid syndrome is a disease of accelerated aging caused by a defect in DNA repair. NF-κB, a transcription factor activated by cellular damage and stress, has increased activity with aging and aging-related chronic diseases. To determine whether NF-κB drives aging in response to the accumulation of spontaneous, endogenous DNA damage, we measured the activation of NF-κB in WT and progeroid model mice. As both WT and progeroid mice aged, NF-κB was activated stochastically in a variety of cell types. Genetic depletion of one allele of the p65 subunit of NF-κB or treatment with a pharmacological inhibitor of the NF-κB-activating kinase, IKK, delayed the age-related symptoms and pathologies of progeroid mice. Additionally, inhibition of NF-κB reduced oxidative DNA damage and stress and delayed cellular senescence. These results indicate that the mechanism by which DNA damage drives aging is due in part to NF-κB activation. IKK/NF-κB inhibitors are sufficient to attenuate this damage and could provide clinical benefit for degenerative changes associated with accelerated aging disorders and normal aging.

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“…Moreover, NF-κB is up-regulated in tissues of aged rodents, specifically in the skin, liver, kidney, cerebellum, cardiac muscle and gastric mucosa (Bregegere et al, 2006;Giardina and Hubbard, 2002;Helenius et al, 1996a;Helenius et al, 1996b;Korhonen et al, 1997;Xiao and Majumdar, 2000). Cells derived from elderly persons and patients with Hutchinson-Gilford progeria, a disease of dramatically accelerated aging, also exhibited increased NF-κB signalling (Adler et al, 2007;Boland, 2001;Kriete et al, 2008). Growing evidence indicates that NF-κB becomes activated in aged tissues in response to accumulated damage and mediates the degenerative changes.…”

Section: Role Of Chronic Activation Of Nf-b In Diseasesmentioning

confidence: 99%

Inflammatory and catabolic signalling in intervertebral discs: The roles of NF-B and MAP Kinases

Wuertz

Kletsas

et al. 2012

eCM

200

198

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Painful intervertebral disc disease is characterised not only by an imbalance between anabolic (i.e., matrix synthesis) and catabolic (i.e., matrix degradation) processes, but also by infl ammatory mechanisms. The increased expression and synthesis of matrix metalloproteinases and infl ammatory factors is mediated by specifi c signal transduction, in particular the nuclear factor-kappaB (NF-B) and mitogen-activated protein kinase (MAPK)-mediated pathways. NF-B and MAPK have been identifi ed as the master regulators of infl ammation and catabolism in several musculoskeletal disorders (e.g., osteoarthritis), and recently growing evidence supports the importance of these signalling pathways in painful disc disease. With continuing research exploiting in vitro and in vivo model systems to elucidate the roles of these pathways in disc degeneration, it may be possible in the near future to specifi cally target these major infl ammatory / catabolic signalling pathways to treat painful degenerative disc disease. In this perspective, we aim to summarise the current state of knowledge concerning the infl ammatory and catabolic molecular pathways of intervertebral disc disease (IDD), with a detailed description of NF-B and MAP kinase-mediated signal transduction in disc cells. Furthermore, we will discuss the emerging novel molecular treatment modalities for IDD using pharmacological inhibitors targeting these pathways.

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Cell autonomous expression of inflammatory genes in biologically aged fibroblasts associated with elevated NF-kappaB activity

Cited by 52 publications

References 49 publications

Alveolar Cell Senescence Exacerbates Pulmonary Inflammation in Patients with Chronic Obstructive Pulmonary Disease

Alveolar Cell Senescence Exacerbates Pulmonary Inflammation in Patients with Chronic Obstructive Pulmonary Disease

NF-κB inhibition delays DNA damage–induced senescence and aging in mice

Inflammatory and catabolic signalling in intervertebral discs: The roles of NF-B and MAP Kinases

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