TGF-β regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells.
TGF-β regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells.
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DOI：
10.1152/ajplung.00134.2010
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发表时间：
2011-02
期刊：
影响因子：
--
通讯作者：
Chung KF
中科院分区：
文献类型：
--
作者：
Michaeloudes C;Sukkar MB;Khorasani NM;Bhavsar PK;Chung KF
活性氧物种(ROS)是细胞正常代谢的结果，主要通过线粒体和过氧化物体产生，但其释放受到氧化酶(如NADPH氧化酶)的激活或内源抗氧化酶(如锰超氧化物歧化酶(MnSOD)和过氧化氢酶(CAT)的下调)的促进。转化生长因子-β(TGFR-β)在哮喘和慢性阻塞性肺疾病患者的气道平滑肌细胞中高表达，可能是这些疾病中气道平滑肌细胞功能异常的关键调节因子。转化生长因子-β在血管内皮细胞炎症反应中的重要作用是诱导IL-6的释放。转化生长因子-β还可通过上调NADPH氧化酶4(NOX4)的表达来促进ASMC内ROS的释放。然而，转化生长因子-β对关键抗氧化酶的表达以及随后对氧化/抗氧化平衡的影响尚不清楚。此外，氧化还原依赖的通路在介导转化生长因子-β在血管平滑肌细胞中的促炎效应中的作用尚不清楚。在本研究中，我们发现转化生长因子-β诱导了NOX4的表达，同时抑制了锰超氧化物歧化酶和过氧化氢酶的表达。这种氧化/抗氧化酶的变化伴随着ROS水平的升高和IL-6的释放。进一步的研究揭示了Smad3和磷脂酰肌醇激酶介导的通路在诱导氧化/抗氧化失衡和IL-6释放中的作用。抗氧化剂N-乙酰半胱氨酸和ebselen通过抑制Smad3的磷酸化，逆转Smad3氧化/抗氧化酶的变化和IL-6的释放，提示转化生长因子-β对Smad3的激活依赖于氧化还原。此外，这些发现表明NAC在防止转化生长因子-β介导的ASMC中的促氧化和促炎反应中具有潜在的作用。用小干扰RNA敲除NOX4可部分阻断MnSOD的抑制作用，但对过氧化氢酶和IL-6的表达无影响。这些发现为转化生长因子-β对ASM功能的氧化还原调节提供了新的见解。
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 phosphatidyl-inositol 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-acetyl-cysteine (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.
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DOI：
10.4049/jimmunol.181.4.2772
发表时间：
2008-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Hollins F;Kaur D;Yang W;Cruse G;Saunders R;Sutcliffe A;Berger P;Ito A;Brightling CE;Bradding P
通讯作者：
Bradding P
DOI：
10.1152/ajplung.2001.280.5.l999
发表时间：
2001-05-01
影响因子：
4.9
作者：
Coutts, A;Chen, G;Khalil, N
通讯作者：
Khalil, N
影响因子：
7.4
作者：
Bakin, AV;Stourman, NV;Freeman, ML
通讯作者：
Freeman, ML
影响因子：
3.6
作者：
Farghaly, Hanan S. M.;Blagbrough, Ian S.;Watson, Malcolm L.
通讯作者：
Watson, Malcolm L.
影响因子：
4.4
作者：
Junn, E;Lee, KN;Choi, I
通讯作者：
Choi, I