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/mend.10.9.8885242
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发表时间：
1996-09
影响因子：
--
通讯作者：
M. Barcellos-Hoff;T. Dix
中科院分区：
文献类型：
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作者：
M. Barcellos-Hoff;T. Dix
转化生长因子β 1（TGF β）是一种多功能细胞因子，通过普遍存在的细胞表面受体协调对损伤的反应。TGF β的生物活性受到其作为潜在复合物（LTGF β）的分泌的抑制，使得活化决定了生理和病理事件期间TGF β活性的程度。TGF β作用已经涉及多种活性氧介导的组织过程，特别是炎症，以及病理学如再灌注损伤、类风湿性关节炎和动脉粥样硬化。它最近被证明是在体内辐射暴露后迅速激活，这也产生活性氧（ROS）。在本研究中，使用无细胞系统研究了氧化还原介导的LTGF β激活的潜力，在该无细胞系统中，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。与标准热活化相比，溶液中重组人LTGF β的辐照（100 Gray）诱导26%的活化。金属催化的抗坏血酸氧化引起非常有效的重组LTGF β激活，匹配或超过热激活。抗坏血酸活化的效率取决于抗坏血酸浓度和过渡金属离子的存在。我们推测，潜伏肽中特定氨基酸的氧化导致潜伏复合物的构象变化，从而释放TGF β。氧化活化为TGF β参与组织过程提供了一种新的途径，其中涉及ROS，并赋予LTGF β作为氧化应激传感器的能力，并通过释放TGF β，作为协调多种细胞类型反应的信号。LTGF β氧化还原敏感性可能是针对体内平衡的恢复;然而，氧化也可能是LTGF β激活的机制，在涉及慢性ROS产生的疾病机制期间可能是有害的。
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 concentrations 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.