TGF-β regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells

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Show simple item record Michaeloudes, C Sukkar, MB Khorasani, NM Bhavsar, PK Chung, KF 2012-10-12T03:33:31Z 2011-02
dc.identifier.citation American Journal of Physiology - Lung Cellular and Molecular Physiology, 2011, 300 (2)
dc.identifier.issn 1040-0605
dc.identifier.other C1UNSUBMIT en_US
dc.description.abstract Reactive oxygen species (ROS) are generated as a result of normal cellular metabolism, mainly through the mitochondria and peroxisomes, but their release is enhanced by the activation of oxidant enzymes such as NADPH oxidases or downregulation of endogenous antioxidant enzymes such as manganese-superoxide dismutase (MnSOD) and catalase. Transforming growth factor-β (TGF-β), found to be overexpressed in airway smooth muscle (ASM) from asthmatic and chronic obstructive pulmonary disease patients, may be a pivotal regulator of abnormal ASM cell (ASMC) function in these diseases. An important effect of TGF-β on ASMC inflammatory responses is the induction of IL-6 release. TGF-β also triggers intracellular ROS release in ASMCs by upregulation of NADPH oxidase 4 (Nox4). However, the effect of TGF-β on the expression of key antioxidant enzymes and subsequently on oxidant/antioxidant balance is unknown. Moreover, the role of redox-dependent pathways in the mediation of the proinflammatory effects of TGF-β in ASMCs is unclear. In this study, we show that TGF-β induced the expression of Nox4 while at the same time inhibiting the expression of MnSOD and catalase. This change in oxidant/antioxidant enzymes was accompanied by elevated ROS levels and IL-6 release. Further studies revealed a role for Smad3 and phosphatidylinositol kinase-mediated pathways in the induction of oxidant/antioxidant imbalance and IL-6 release. The changes in oxidant/antioxidant enzymes and IL-6 release were reversed by the antioxidants N-acetylcysteine (NAC) and ebselen through inhibition of Smad3 phosphorylation, indicating redox-dependent activation of Smad3 by TGF-β. Moreover, these findings suggest a potential role for NAC in preventing TGF-β-mediated pro-oxidant and proinflammatory responses in ASMCs. Knockdown of Nox4 using small interfering RNA partially prevented the inhibition of MnSOD but had no effect on catalase and IL-6 expression. These findings provide novel insights into redox regulation of ASM function by TGF-β. Copyright © 2011 the American Physiological Society.
dc.language eng
dc.relation.isbasedon 10.1152/ajplung.00134.2010
dc.title TGF-β regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells
dc.type Journal Article
dc.parent American Journal of Physiology - Lung Cellular and Molecular Physiology
dc.journal.volume 2
dc.journal.volume 300
dc.journal.number en_US
dc.publocation Bethesda, MD, USA en_US
dc.identifier.startpage 295 en_US
dc.identifier.endpage 304 en_US GSH.Pharmacy en_US
dc.conference Verified OK en_US
dc.for 1116 Medical Physiology
dc.for 0606 Physiology
dc.personcode 113444
dc.percentage 50 en_US Physiology en_US
dc.classification.type FOR-08 en_US
dc.edition en_US
dc.custom en_US en_US
dc.location.activity en_US
dc.description.keywords Manganese-superoxide dismutase
dc.description.keywords N-acetyl cysteine
dc.description.keywords NADPH oxidase 4 (nox4)
dc.description.keywords Phosphatidyl-inositol kinases
dc.description.keywords Reactive oxygen species
dc.description.keywords Smad
dc.description.keywords Transforming growth factor-β
pubs.embargo.period Not known
pubs.organisational-group /University of Technology Sydney
pubs.organisational-group /University of Technology Sydney/Graduate School of Health
utslib.copyright.status Closed Access 2015-04-15 12:17:09.805752+10
pubs.consider-herdc false
utslib.collection.history Closed (ID: 3)
utslib.collection.history Uncategorised (ID: 363)

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