Molecular and Cellular Biology

NADPH Oxidases

Publications

Publications

Main Representative Publications

Xavier De Deken:    

  • Autophagy regulates DUOX1 localization and superoxide production in airway epithelial cells during chronic IL-13 stimulation.

    Autophagy regulates DUOX1 localization and superoxide production in airway epithelial cells during chronic IL-13 stimulation.

    Redox Biol. 2017 Sep 22;14:272-284

    Authors: Dickinson JD, Sweeter JM, Warren KJ, Ahmad IM, De Deken X, Zimmerman MC, Brody SL

    Abstract
    The airway epithelium is a broad interface with the environment, mandating well-orchestrated responses to properly modulate inflammation. Classically, autophagy is a homeostatic pathway triggered in response to external cellular stresses, and is elevated in chronic airway diseases. Recent findings highlight the additional role of autophagy in vesicle trafficking and protein secretion, implicating autophagy pathways in complex cellular responses in disease. Th2 cytokines, IL-13 and IL-4, are increased in asthma and other airway diseases contributing to chronic inflammation. Previously, we observed that IL-13 increases reactive oxygen species (ROS) in airway epithelial cells in an autophagy-dependent fashion. Here, we tested our hypothesis that autophagy is required for IL-13-mediated superoxide production via the NADPH oxidase DUOX1. Using a mouse model of Th2-mediated inflammation induced by OVA-allergen, we observed elevated lung amounts of IL-13 and IL-4 accompanied by increased autophagosome levels, determined by LC3BII protein levels and immunostaining. ROS levels were elevated and DUOX1 expression was increased 70-fold in OVA-challenged lungs. To address the role of autophagy and ROS in the airway epithelium, we treated primary human tracheobronchial epithelial cells with IL-13 or IL-4. Prolonged, 7-day treatment increased autophagosome formation and degradation, while brief activation had no effect. Under parallel culture conditions, IL-13 and IL-4 increased intracellular superoxide levels as determined by electron paramagnetic resonance (EPR) spectroscopy. Prolonged IL-13 activation increased DUOX1, localized at the apical membrane. Silencing DUOX1 by siRNA attenuated IL-13-mediated increases in superoxide, but did not reduce autophagy activities. Notably, depletion of autophagy regulatory protein ATG5 significantly reduced superoxide without diminishing total DUOX1 levels. Depletion of ATG5, however, diminished DUOX1 localization at the apical membrane. The findings suggest non-canonical autophagy activity regulates DUOX1-dependent localization required for intracellular superoxide production during Th2 inflammation. Thus, in chronic Th2 inflammatory airway disease, autophagy proteins may be responsible for persistent intracellular superoxide production.

    PMID: 28982074 [PubMed - as supplied by publisher]

 

 

Françoise Miot:        

 

Bernard Corvilain:  

  • T2-weighted MRI signal predicts hormone and tumor responses to somatostatin analogs in acromegaly.
    Related Articles

    T2-weighted MRI signal predicts hormone and tumor responses to somatostatin analogs in acromegaly.

    Endocr Relat Cancer. 2016 Nov;23(11):871-881

    Authors: Potorac I, Petrossians P, Daly AF, Alexopoulou O, Borot S, Sahnoun-Fathallah M, Castinetti F, Devuyst F, Jaffrain-Rea ML, Briet C, Luca F, Lapoirie M, Zoicas F, Simoneau I, Diallo AM, Muhammad A, Kelestimur F, Nazzari E, Centeno RG, Webb SM, Nunes ML, Hana V, Pascal-Vigneron V, Ilovayskaya I, Nasybullina F, Achir S, Ferone D, Neggers SJ, Delemer B, Petit JM, Schöfl C, Raverot G, Goichot B, Rodien P, Corvilain B, Brue T, Schillo F, Tshibanda L, Maiter D, Bonneville JF, Beckers A

    Abstract
    GH-secreting pituitary adenomas can be hypo-, iso- or hyper-intense on T2-weighted MRI sequences. We conducted the current multicenter study in a large population of patients with acromegaly to analyze the relationship between T2-weighted signal intensity on diagnostic MRI and hormonal and tumoral responses to somatostatin analogs (SSA) as primary monotherapy. Acromegaly patients receiving primary SSA for at least 3 months were included in the study. Hormonal, clinical and general MRI assessments were performed and assessed centrally. We included 120 patients with acromegaly. At diagnosis, 84, 17 and 19 tumors were T2-hypo-, iso- and hyper-intense, respectively. SSA treatment duration, cumulative and mean monthly doses were similar in the three groups. Patients with T2-hypo-intense adenomas had median SSA-induced decreases in GH and IGF-1 of 88% and 59% respectively, which were significantly greater than the decreases observed in the T2-iso- and hyper-intense groups (P < 0.001). Tumor shrinkage on SSA was also significantly greater in the T2-hypo-intense group (38%) compared with the T2-iso- and hyper-intense groups (8% and 3%, respectively; P < 0.0001). The response to SSA correlated with the calculated T2 intensity: the lower the T2-weighted intensity, the greater the decrease in random GH (P < 0.0001, r = 0.22), IGF-1 (P < 0.0001, r = 0.14) and adenoma volume (P < 0.0001, r = 0.33). The T2-weighted signal intensity of GH-secreting adenomas at diagnosis correlates with hormone reduction and tumor shrinkage in response to primary SSA treatment in acromegaly. This study supports its use as a generally available predictive tool at diagnosis that could help to guide subsequent treatment choices in acromegaly.

    PMID: 27649724 [PubMed - indexed for MEDLINE]

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