Increased nuclear factor κB activation in critically ill patients who die

Paterson, Ross L; Galley, Helen F.; Dhillon, Jatinder Kaur; Webster, Nigel R.

doi:10.1097/00003246-200004000-00022

Cited by 94 publications

(55 citation statements)

References 22 publications

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“…Greatly diminished NF-kB responsiveness, as occurs in rare human primary immunodeficiencies caused by genetic mutations affecting NF-kB activation, results in recurrent, severe infections. At the other end of the spectrum, excessive inflammation can also be very harmful, with clinical data suggesting a pathologic role for NF-kB in sepsis and multiple-organ failure (46,47). Similarly, our data indicate that NFKBIA promoter variants associated with increased TLR-mediated inflammatory responses are associated with severe RSV bronchiolitis and AHR in children with positive nasal swabs for RSV or PIV in the first year of life (Table V).…”

Section: Discussionsupporting

confidence: 67%

Functional Genetic Variation inNFKBIAand Susceptibility to Childhood Asthma, Bronchiolitis, and Bronchopulmonary Dysplasia

Ali

Hirschfeld

Mayer

et al. 2013

The Journal of Immunology

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Respiratory diseases are the most frequent chronic illnesses in babies and children. Although a vigorous innate immune system is critical for maintaining lung health, a balanced response is essential to minimize damaging inflammation. We investigated the functional and clinical impact of human genetic variants in the promoter of NFKBIA, which encodes IκBα, the major negative regulator of NF-κB. In this study, we quantified the functional impact of NFKBIA promoter polymorphisms (rs3138053, rs2233406, and rs2233409) on promoter-driven protein expression, allele-specific and total NFKBIA mRNA expression, IκBα protein expression, and TLR responsiveness; mapped innate immune regulatory networks active during respiratory syncytial virus infection, asthma, and bronchopulmonary dysplasia; and genotyped and analyzed independent cohorts of children with respiratory syncytial virus infection, asthma, and bronchopulmonary dysplasia. Genetic variants in the promoter of NFKBIA influenced NFKBIA gene expression, IκBα protein expression, and TLR-mediated inflammatory responses. Using a systems biology approach, we demonstrated that NFKBIA/IκBα is a central hub in transcriptional responses of prevalent childhood lung diseases, including respiratory syncytial virus infection, asthma, and bronchopulmonary dysplasia. Finally, by examining independent pediatric lung disease cohorts, we established that this immunologically relevant genetic variation in the promoter of NFKBIA is associated with differential susceptibility to severe bronchiolitis following infection with respiratory syncytial virus, airway hyperresponsiveness, and severe bronchopulmonary dysplasia. These data highlight the importance of negative innate immune regulators, such as NFKBIA, in pediatric lung disease and begin to unravel common aspects in the genetic predisposition to bronchopulmonary dysplasia, bronchiolitis, and childhood asthma.

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Section: Discussionsupporting

confidence: 67%

Functional Genetic Variation inNFKBIAand Susceptibility to Childhood Asthma, Bronchiolitis, and Bronchopulmonary Dysplasia

Ali

Hirschfeld

Mayer

et al. 2013

The Journal of Immunology

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“…(Baeuerle, 1998;Karin and Delhase, 2000). With particular clinical relevance, NF-B binding activity has been found to be increased in patients with acute inflammation and sepsis and to be correlated with clinical severity and mortality (Bohrer et al, 1997;Arnalich et al, 2000;Paterson et al, 2000). Under the experimental conditions used in our laboratory, we found that activation of the NF-B pathway is a very early event, because IB␣ is degraded and NF-B is activated already at 15 min after endotoxin administration.…”

Section: Discussionmentioning

confidence: 62%

Parthenolide, an Inhibitor of the Nuclear Factor-κB Pathway, Ameliorates Cardiovascular Derangement and Outcome in Endotoxic Shock in Rodents

et al. 2002

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Parthenolide is a sesquiterpene lactone used in folk medicine for its anti-inflammatory activity. Recent in vitro studies have shown that this compound inhibits the nuclear factor (NF)-B pathway. This study examines the effect of parthenolide in endotoxic shock in rodents. Endotoxic shock was induced by administration of Escherichia coli endotoxin in rats. Three groups of rats received parthenolide (0.25, 0.5, or 1 mg/kg) 15 min before endotoxin; another group received parthenolide (1 mg/kg) 3 h after endotoxin. In vehicle-treated rats, administration of endotoxin caused severe hypotension, which was associated with a marked hyporeactivity to norepinephrine in ex vivo thoracic aortas. Immunohistochemistry showed positive staining for nitrotyrosine, poly(ADP-ribose) synthetase (PARS) and apoptosis, whereas Northern blot analysis showed increased mRNA expression of inducible nitric-oxide synthase (iNOS) in thoracic aortas. Elevated levels of plasma nitrate/ nitrite were also found. Elevated lung levels of myeloperoxidase activity were indicative of infiltration of neutrophils. These inflammatory events were preceded by cytosolic degradation of inhibitor B␣ (IB␣) and activation of nuclear NF-B in the lung. In vivo pretreatment and post-treatment with parthenolide improved the hemodynamic profile and reduced plasma nitrate/ nitrite and lung neutrophil infiltration in a dose-dependent fashion. Vascular hyporeactivity of ex vivo aortas was ameliorated. Treatment with parthenolide also abolished nitrotyrosine formation, PARS expression, and apoptosis and reduced iNOS mRNA content in thoracic aortas. DNA binding of NF-B was inhibited by parthenolide in the lung, whereas degradation of IB␣ was unchanged. In a separate set of experiments, pretreatment or post-treatment with parthenolide significantly improved survival in mice challenged with endotoxin. We conclude that parthenolide exerts beneficial effects during endotoxic shock through inhibition of NF-B.

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“…A role for NFB has been implicated in the pathophysiology of sepsis, ARDS, and SIRS through enhanced gene expression of proinflammatory cytokines, chemokines, adhesion molecules, and inducible nitric oxide synthase and by the attenuation of phagocytic cell apoptosis (1,6,7,9,32,44). Enhanced NFB activation has been reported in patients with sepsis, SIRS, and ARDS and is correlated with poor outcome and increased mortality (7,32,44). Inhibition of NFB enhances spontaneous neutrophil apoptosis, suggesting that activation of NFB may be an important regulatory site in control of neutrophil apoptosis (42,55).…”

Section: Discussionmentioning

confidence: 99%

“…TNF-␣ is a potent activator of NFB, a family of transcription factors thought to have a critical role in cell survival through the induction of antiapoptotic genes (1,6,7,9,32,44,55). Neutrophil NFB activation requires the translocation of the p50 and p65 NFB subunits to the nucleus.…”

Section: Effect Of Tnf-␣ On Spontaneous Neutrophil Apoptosismentioning

confidence: 99%

A role for PKC-δ and PI 3-kinase in TNF-α-mediated antiapoptotic signaling in the human neutrophil

Kilpatrick

Lee

Haines

et al. 2002

American Journal of Physiology-Cell Physiology

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The proinflammatory cytokine tumor necrosis factor (TNF)-α has been implicated in the attenuation of neutrophil spontaneous apoptosis during sepsis. Antiapoptotic signaling is principally mediated through the p60TNF receptor (p60TNFR). In neutrophils, TNF-α is an incomplete secretagogue and requires input from a ligated integrin(s) for neutrophil activation. In adherent neutrophils, TNF-α triggers association of both protein kinase C (PKC)-δ and phosphatidylinositol (PI) 3-kinase with the p60TNFR. In this study, a role for PKC-δ and PI 3-kinase in TNF-α-mediated antiapoptotic signaling was examined. TNF-α inhibited spontaneous apoptosis in fibronectin-adherent neutrophils, and this antiapoptotic signaling was blocked by the PKC-δ inhibitor rottlerin, but not by an inhibitor of Ca2+-dependent PKC isotypes, Go-6976. Inhibition of PI 3-kinase by LY-294002 also inhibited TNF-α-mediated antiapoptotic signaling. Cycloheximide blocked TNF-α-mediated antiapoptotic signaling, suggesting protein synthesis is required. Inhibition of either PKC-δ or PI 3-kinase attenuated TNF-α-mediated activation of the antiapoptotic transcription factor NFκB. Thus both PKC-δ and PI 3-kinase have essential roles in TNF-α-mediated antiapoptotic signaling in adherent neutrophils.

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Increased nuclear factor κB activation in critically ill patients who die

Cited by 94 publications

References 22 publications

Functional Genetic Variation inNFKBIAand Susceptibility to Childhood Asthma, Bronchiolitis, and Bronchopulmonary Dysplasia

Functional Genetic Variation inNFKBIAand Susceptibility to Childhood Asthma, Bronchiolitis, and Bronchopulmonary Dysplasia

Parthenolide, an Inhibitor of the Nuclear Factor-κB Pathway, Ameliorates Cardiovascular Derangement and Outcome in Endotoxic Shock in Rodents

A role for PKC-δ and PI 3-kinase in TNF-α-mediated antiapoptotic signaling in the human neutrophil

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