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

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dc.contributor.author Michaeloudes, Charalambos en_US
dc.contributor.author Sukkar, Maria en_US
dc.contributor.author Khorasani, Nadia en_US
dc.contributor.author Bhavsar, Pankaj en_US
dc.contributor.editor en_US
dc.date.accessioned 2012-10-12T03:33:31Z
dc.date.available 2012-10-12T03:33:31Z
dc.date.issued 2011 en_US
dc.identifier 2011002351 en_US
dc.identifier.citation Michaeloudes Charalambos et al. 2011, 'TGF-B regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells', American Physiological Society, vol. 300, pp. 295-304. en_US
dc.identifier.issn 1040-0605 en_US
dc.identifier.other C1UNSUBMIT en_US
dc.identifier.uri http://hdl.handle.net/10453/18186
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-B (TGF-B), 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-B on ASMC inflammatory responses is the induction of IL-6 release. TGF-B also triggers intracellular ROS release in ASMCs by upregulation of NADPH oxidase 4 (Nox4). However, the effect of TGF-B on the expression of key antioxidant enzymes and subsequently on oxidant/antioxidant balance is unknown. Moreover, the role of redoxdependent pathways in the mediation of the proinflammatory effects of TGF-B in ASMCs is unclear. In this study, we show that TGF-B 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-B. Moreover, these findings suggest a potential role for NAC in preventing TGF-B-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 redo regulation of ASM function by TGF-B. en_US
dc.language en_US
dc.publisher American Physiological Society en_US
dc.title TGF-B regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells en_US
dc.parent American Journal of Physiology: Lung Cellular and Molecular Physiology en_US
dc.journal.volume 300 en_US
dc.journal.number en_US
dc.publocation Bethesda, MD, USA en_US
dc.identifier.startpage 295 en_US
dc.identifier.endpage 304 en_US
dc.cauo.name GSH.Pharmacy en_US
dc.conference Verified OK en_US
dc.for 060600 en_US
dc.personcode 0000074186 en_US
dc.personcode 113444 en_US
dc.personcode 0000074187 en_US
dc.personcode 0000074188 en_US
dc.percentage 50 en_US
dc.classification.name Physiology en_US
dc.classification.type FOR-08 en_US
dc.edition en_US
dc.custom en_US
dc.date.activity en_US
dc.location.activity en_US
dc.description.keywords Smad, phosphatidyl-inositol kinases, reactive oxygen species, N-acetyl cysteine, manganese-superoxide dismutase, transforming growth factor-B, NADPH oxidase 4 (Nox4) en_US


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