title: Apocynin and Nox2 regulate NF-κB by modifying thioredoxin-1 redox-state.
abstract: The reactive-oxygen-species-(ROS)-generating-enzyme Nox2 is essential for leukocyte anti-microbial activity. However its role in cellular redox homeostasis and, consequently, in modulating intracellular signaling pathways remains unclear. Herein, we show Nox2 activation favors thioredoxin-1 (TRX-1)/p40phox interaction, which leads to exclusion of TRX-1 from the nucleus. In contrast, the genetic deficiency of Nox2 or its pharmacological inhibition with apocynin (APO) results in reductive stress after lipopolysaccharide-(LPS)-cell stimulation, which causes nuclear accumulation of TRX-1 and enhanced transcription of inflammatory mediators through nuclear-factor-(NF)-κB. The NF-κB overactivation is prevented by TRX-1 oxidation using inhibitors of thioredoxin reductase-1 (TrxR-1). The Nox2/TRX-1/NF-κB intracellular signaling pathway is involved in the pathophysiology of chronic granulomatous disease (CGD) and sepsis. In fact, TrxR-1 inhibition prevents nuclear accumulation of TRX-1 and LPS-stimulated hyperproduction of tumor-necrosis-factor-(TNF)-α by monocytes and neutrophils purified from blood of CGD patients, who have deficient Nox2 activity. TrxR-1 inhibitors, either lanthanum chloride (LaCl3) or auranofin (AUR), also increase survival rates of mice undergoing cecal-ligation-and-puncture-(CLP). Therefore, our results identify a hitherto unrecognized Nox2-mediated intracellular signaling pathway that contributes to hyperinflammation in CGD and in septic patients. Additionally, we suggest that TrxR-1 inhibitors could be potential drugs to treat patients with sepsis, particularly in those with CGD.
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto, Brazil.|Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil.|King's College London, British Heart Foundation Centre, Cardiovascular Division, London, United Kingdom.
authors.forename: Silvia Cellone
authors.initials: SC
authors.lastname: Trevelin
authors.affiliation: King's College London, British Heart Foundation Centre, Cardiovascular Division, London, United Kingdom.
authors.forename: Célio Xavier
authors.initials: CX
authors.lastname: Dos Santos
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto, Brazil.
authors.forename: Raphael Gomes
authors.initials: RG
authors.lastname: Ferreira
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil.
authors.forename: Larissa
authors.initials: L
authors.lastname: de Sá Lima
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto, Brazil.
authors.forename: Rangel Leal
authors.initials: RL
authors.lastname: Silva
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil.
authors.forename: Cristoforo
authors.initials: C
authors.lastname: Scavone
authors.affiliation: Department of Biophysics and Physiology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil.
authors.forename: Rui
authors.initials: R
authors.lastname: Curi
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto, Brazil.
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Alves-Filho
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto, Brazil.
authors.forename: Thiago Mattar
authors.initials: TM
authors.lastname: Cunha
authors.affiliation: Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto, Brazil.
authors.forename: Pérsio
authors.initials: P
authors.lastname: Roxo-Júnior
authors.affiliation: Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto, Brazil.
authors.forename: Maria-Célia
authors.initials: MC
authors.lastname: Cervi
authors.affiliation: Heart Institute, School of Medicine, University of Sao Paulo, São Paulo, Brazil.
authors.forename: Francisco Rafael Martins
authors.initials: FR
authors.lastname: Laurindo
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto, Brazil.
authors.forename: John Stephen
authors.initials: JS
authors.lastname: Hothersall
authors.affiliation: King's College London, British Heart Foundation Centre, Cardiovascular Division, London, United Kingdom.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Cobb
authors.affiliation: King's College London, British Heart Foundation Centre, Cardiovascular Division, London, United Kingdom.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: King's College London, British Heart Foundation Centre, Cardiovascular Division, London, United Kingdom.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Ivetic
authors.affiliation: King's College London, British Heart Foundation Centre, Cardiovascular Division, London, United Kingdom.
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil.
authors.forename: Lucia Rossetti
authors.initials: LR
authors.lastname: Lopes
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto, Brazil.
authors.forename: Fernando Queiroz
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D006105:Granulomatous Disease, Chronic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D018805:Sepsis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000098:Acetophenones; D008070:Lipopolysaccharides; D016328:NF-kappa B; C515559:Txn1 protein, mouse; D013879:Thioredoxins; C056165:acetovanillone; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2