Hypoxia induces calpain activity and degrades SMAD2 to attenuate TGFβ signaling in macrophages.
Hypoxia induces calpain activity and degrades SMAD2 to attenuate TGFβ signaling in macrophages.
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DOI：
10.1186/s13578-015-0026-x
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发表时间：
2015
影响因子：
7.5
通讯作者：
Brüne B
中科院分区：
文献类型：
--
作者：
Cui W;Zhou J;Dehne N;Brüne B
在炎症条件下或肿瘤进展期间，巨噬细胞获得不同的表型，微环境因素如缺氧和转化生长因子β（TGFβ）塑造其功能可塑性。TGFβ是引起替代性巨噬细胞活化的因素之一，其有助于组织再生，从而缓解炎症，但也可能引起肿瘤进展。然而，TGFβ和缺氧之间的信号串扰尚不清楚。将人原代巨噬细胞暴露于TGFβ引起SMAD 2/SMAD 3快速磷酸化。这种早期TGFβ信号传导不受缺氧的影响。然而，随着TGFβ/缺氧暴露时间的延长，SMAD 2的表达由于蛋白质稳定性降低而下降。与此同时，缺氧增加了钙蛋白酶调节亚基的mRNA和蛋白量，进一步认为TGFβ/缺氧引起钙蛋白酶激活。双重特异性蛋白酶体/钙蛋白酶抑制剂MG 132和特异性钙蛋白酶抑制剂1挽救了SMAD 2降解，证实了钙蛋白酶降解SMAD 2的能力。SMAD 2表达减少会降低其靶基因血小板反应蛋白1、肌张力障碍蛋白和基质金属蛋白酶2的TGFβ转录活性。缺氧通过钙蛋白酶介导的中央信号组分SMAD 2的蛋白水解干扰巨噬细胞中的TGFβ信号传导。本文的在线版本（doi：10.1186/s13578-015-0026-x）包含补充材料，可供授权用户使用。
Under inflammatory conditions or during tumor progression macrophages acquire distinct phenotypes, with factors of the microenvironment such as hypoxia and transforming growth factor β (TGFβ) shaping their functional plasticity. TGFβ is among the factors causing alternative macrophage activation, which contributes to tissue regeneration and thus, resolution of inflammation but may also provoke tumor progression. However, the signal crosstalk between TGFβ and hypoxia is ill defined. Exposing human primary macrophages to TGFβ elicited a rapid SMAD2/SMAD3 phosphorylation. This early TGFβ-signaling remained unaffected by hypoxia. However, with prolonged exposure periods to TGFβ/hypoxia the expression of SMAD2 declined because of decreased protein stability. In parallel, hypoxia increased mRNA and protein amount of the calpain regulatory subunit, with the further notion that TGFβ/hypoxia elicited calpain activation. The dual specific proteasome/calpain inhibitor MG132 and the specific calpain inhibitor 1 rescued SMAD2 degradation, substantiating the ability of calpain to degrade SMAD2. Decreased SMAD2 expression reduced TGFβ transcriptional activity of its target genes thrombospondin 1, dystonin, and matrix metalloproteinase 2. Hypoxia interferes with TGFβ signaling in macrophages by calpain-mediated proteolysis of the central signaling component SMAD2. The online version of this article (doi:10.1186/s13578-015-0026-x) contains supplementary material, which is available to authorized users.
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DOI：
10.4049/jimmunol.181.8.5646
发表时间：
2008-10-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Jennewein C;Kuhn AM;Schmidt MV;Meilladec-Jullig V;von Knethen A;Gonzalez FJ;Brüne B
通讯作者：
Brüne B
影响因子：
4.8
作者：
DESHPANDE, RV;GOUST, JM;BANIK, NL
通讯作者：
BANIK, NL
影响因子：
4.1
作者：
Kuratomi, G;Komuro, A;Imamura, T
通讯作者：
Imamura, T
影响因子：
8
作者：
Kretschmer, A;Moepert, K;Klippel, A
通讯作者：
Klippel, A
影响因子：
8
作者：
Chae, K. S.;Kang, M. J.;Chi, S. G.
通讯作者：
Chi, S. G.