Redox-mediated activation of latent transforming growth factor-beta 1
Redox-mediated activation of latent transforming growth factor-beta 1
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DOI：
10.1210/me.10.9.1077
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发表时间：
1996-09-01
影响因子：
--
通讯作者：
Dix, TA
中科院分区：
文献类型：
--
作者：
BarcellosHoff, MH;Dix, TA
转化生长因子β1是一种多功能细胞因子，它通过普遍存在的细胞表面受体来协调对损伤的反应。转化生长因子β的生物活性受其分泌的潜在复合体(LTGFβ)的抑制，在生理和病理过程中，激活决定了转化生长因子β的活性程度。转化生长因子β的作用涉及到多种由活性氧介导的组织过程，特别是炎症，以及再灌注损伤、类风湿性关节炎和动脉粥样硬化等病理过程。最近有研究表明，在体内辐射后，它会迅速被激活，这也会产生活性氧物种(ROS)。在本研究中，通过电离辐射或金属离子催化的抗坏血酸反应在溶液中产生ROS的无细胞体系中研究了氧化还原介导的LTGF-β激活的可能性，辐射(100Gray)溶液中的重组人LTGF-β的激活是标准热激活的26%，金属催化的抗坏血酸氧化诱导了与热激活相匹配或超过热激活的高效的重组LTGF-β的激活。抗坏血酸的活化效率取决于抗坏血酸的浓度和过渡金属离子的存在。我们推测，潜伏期授予肽中特定氨基酸的氧化导致潜伏期复合体的构象变化，从而允许释放转化生长因子β。氧化激活为转化生长因子β参与ROS参与的组织过程提供了一条新的途径，并赋予转化生长因子β作为氧化应激传感器的能力，并通过释放转化生长因子β作为信号来协调多种类型的细胞的反应。LTGFβ氧化还原敏感性可能与体内平衡的恢复有关；然而，氧化也可能是LTGFβ激活的一种机制，在涉及慢性ROS产生的疾病机制中可能是有害的。
Transforming growth factor beta 1 (TGF beta) is a multifunctional cytokine that orchestrates response to injury via ubiquitous cell surface receptors. The biological activity of TGF beta is restrained by its secretion as a latent complex (LTGF beta) such that activation determines the extent of TGF beta activity during physiological and pathological events, TGF beta action has been implicated in a variety of reactive oxygen-mediated tissue processes, particularly inflammation, and in pathologies such as reperfusion injury, rheumatoid arthritis, and atherosclerosis. It was recently shown to be rapidly activated after in vivo radiation exposure, which also generates reactive oxygen species (ROS). In the present studies, the potential for redox-mediated LTGF beta activation was investigated using a cell-free system in which ROS were generated in solution by ionizing radiation or metal ion-catalyzed ascorbate reaction, Irradiation (100 Gray) of recombinant human LTGF beta in solution induced 26% activation compared with that elicited by standard thermal activation, Metal-catalyzed ascorbate oxidation elicited extremely efficient recombinant LTGF beta activation that matched or exceeded thermal activation. The efficiency of ascorbate activation depended on ascorbate concentration and the presence of transition metal ions. We postulate that oxidation of specific amino acids in the latency-conferring peptide leads to a conformation change in the latent complex that allows release of TGF beta. Oxidative activation offers a novel route for the involvement of TGF beta in tissue processes in which ROS are implicated and endows LTGF beta with the ability to act as a sensor of oxidative stress and, by releasing TGF beta, to function as a signal for orchestrating the response of multiple cell types. LTGF beta redox sensitivity is presumably directed toward recovery of homeostasis; however, oxidation may also be a mechanism of LTGF beta activation that can be deleterious during disease mechanisms involving chronic ROS production.