Redox-control of the alarmin, Interleukin-1α.
Redox-control of the alarmin, Interleukin-1α.
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DOI：
10.1016/j.redox.2013.03.001
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发表时间：
2013
期刊：
影响因子：
11.4
通讯作者：
Melendez, J. Andres
中科院分区：
文献类型：
--
作者：
McCarthy, Donald A.;Ranganathan, Aparna;Subbaram, Sita;Flaherty, Nicole L.;Patel, Nilay;Trebak, Mohamed;Hempel, Nadine;Melendez, J. Andres
关键词：
促炎症细胞因子白介素1α(IL-1α)是一种与氧化应激相关的多种炎症性疾病的易感标记物，包括阿尔茨海默氏症、关节炎、动脉粥样硬化、糖尿病和癌症。在本研究中，我们证实IL-1α的表达和核定位是氧化还原依赖的。由于锰超氧化物歧化酶(SOD2)的强制表达，导致稳态H_2O_2浓度(SS-[H_2O_2])的变化，从而推动IL-1α基因和蛋白的表达。IL-1α的氧化还原依赖性表达伴随着其核定位的增加。过氧化氢酶共表达可抑制IL-1α的表达及其核内滞留。亚致死剂量的H_2O_2也会导致IL-1α的核定位。诱变实验表明，IL-1α的核定位不涉及其N端区半胱氨酸的氧化。即使在过氧化氢存在的情况下，抑制加工酶Calain也可以阻止IL-1α的核定位。H_2O_2处理引起细胞外Ca~(2+)内流，提示氧化剂可能通过细胞外Ca~(2+)动员间接影响CaP活性。在功能上，由于其核的活性，IL-1α的过表达促进了核因子-kB的活性，但也与组蛋白乙酰转移酶(HAT)p300相互作用。总之，这些发现证明了氧化剂通过IL-1α影响炎症的机制，并表明基于抗氧化剂的治疗在限制炎症性疾病进展方面可能被证明是有用的。SOD2依赖的稳态H_2O_2增加促进IL-1α的表达。H_2O_2引起IL-1α的核定位和细胞外钙内流。抑制Ca~(2+)调节的Calain可阻止H_2O_2依赖的IL-1α核定位。核内IL-1α与p300相互作用，促进核因子-κB活性。
The pro-inflammatory cytokine Interleukin-1α (IL-1α) has recently emerged as a susceptibility marker for a wide array of inflammatory diseases associated with oxidative stress including Alzheimer's, arthritis, atherosclerosis, diabetes and cancer. In the present study, we establish that expression and nuclear localization of IL-1α are redox-dependent. Shifts in steady-state H2O2 concentrations (SS-[H2O2]) resulting from enforced expression of manganese superoxide dismutase (SOD2) drive IL-1α mRNA and protein expression. The redox-dependent expression of IL-1α is accompanied by its increased nuclear localization. Both IL-1α expression and its nuclear residency are abrogated by catalase co-expression. Sub-lethal doses of H2O2 also cause IL-1α nuclear localization. Mutagenesis revealed IL-1α nuclear localization does not involve oxidation of cysteines within its N terminal domain. Inhibition of the processing enzyme calpain prevents IL-1α nuclear localization even in the presence of H2O2. H2O2 treatment caused extracellular Ca2+ influx suggesting oxidants may influence calpain activity indirectly through extracellular Ca2+ mobilization. Functionally, as a result of its nuclear activity, IL-1α overexpression promotes NF-kB activity, but also interacts with the histone acetyl transferase (HAT) p300. Together, these findings demonstrate a mechanism by which oxidants impact inflammation through IL-1α and suggest that antioxidant-based therapies may prove useful in limiting inflammatory disease progression. Sod2-dependent increases in steady-state H2O2 promote IL-1α expression. H2O2 causes nuclear localization of IL-1α and extracellular Ca2+ influx. Inhibition of the Ca2+ regulated calpain prevents H2O2 dependent IL-1α nuclear localization. Nuclear IL-1α interacts with p300 and promotes NF-κB activity.
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影响因子：
3.9
作者：
KUMAR, S;VINCI, JM;BAGLIONI, C
通讯作者：
BAGLIONI, C
影响因子：
16
作者：
Afonina IS;Tynan GA;Logue SE;Cullen SP;Bots M;Lüthi AU;Reeves EP;McElvaney NG;Medema JP;Lavelle EC;Martin SJ
通讯作者：
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影响因子：
12.4
作者：
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通讯作者：
Carvalho, C. M.
影响因子：
4.8
作者：
Buryskova, M;Pospisek, M;Burysek, L
通讯作者：
Burysek, L
DOI：
10.1152/ajpheart.00699.2006
发表时间：
2007-01-01
影响因子：
4.8
作者：
Hoffman, David L.;Salter, Jason D.;Brookes, Paul S.
通讯作者：
Brookes, Paul S.