The TGF-β Superfamily Cytokine MIC-1/GDF15: Secretory Mechanisms Facilitate Creation of Latent Stromal Stores
The TGF-β Superfamily Cytokine MIC-1/GDF15: Secretory Mechanisms Facilitate Creation of Latent Stromal Stores
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DOI：
10.1089/jir.2009.0052
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发表时间：
2010-06-01
影响因子：
2.3
通讯作者：
Breit, Samuel N.
中科院分区：
文献类型：
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作者：
Bauskin, Asne R.;Jiang, Lele;Breit, Samuel N.
巨噬细胞抑制细胞因子-1/生长分化因子15 （MIC-1/GDF15）是tgf - β超家族的一个不同成员，由一系列促炎细胞因子和氧化低密度脂蛋白（oxLDL）诱导，在动脉粥样硬化和肿瘤病变的巨噬细胞中高表达。MIC-1/GDF15是p53的主要靶基因，主要被描述为具有抗肿瘤活性，最近在晚期癌症中，高MIC-1/GDF15血清水平被证明是癌症相关体重减轻的主要原因。MIC-1/GDF15血清水平独立预测动脉粥样硬化事件和类风湿关节炎（RA）的严重程度，提示血清水平在调节疾病表达方面很重要。控制血清水平的是潜伏的未加工的MIC-1/GDF15基质储存与细胞产生的可溶性成熟MIC-1/GDF15的比率。在这里，我们研究了U937单核细胞MIC-1/GDF15的分泌，并确定了旨在确保未加工细胞因子的分泌和潜在基质储存的产生的新机制。我们发现内源性MIC-1/GDF15以加工和未加工的形式分泌。MIC-1/GDF15分泌的脉冲追踪分析显示，未加工的MIC-1/GDF15前体分泌迅速，而细胞内加工产生的成熟的MIC-1/GDF15分泌速度要慢得多，可能是通过另一种分泌途径。前肽的cooh - t47氨基酸负责MIC-1/GDF15前体的快速分泌，这种作用发生在反式高尔基网络(TGN)/后TGN隔室中。因此，MIC-1/GDF15细胞内加工的变化，调节前肽的存在或不存在，是调节MIC-1/GDF15分泌率和proMIC-1/GDF15基质储存率的强大机制，对成熟的MIC-1/GDF15循环水平有主要影响。
Macrophage inhibitory cytokine-1/growth differentiation factor 15 (MIC-1/GDF15), a divergent member of the TGF-beta superfamily is induced by a range of proinflammatory cytokines and oxidized low-density lipoprotein (oxLDL) and is highly expressed in macrophages in atherosclerotic and tumor lesions. MIC-1/GDF15, a major p53 target gene, is largely described to have anti-tumorigenic activity and more recently high MIC-1/GDF15 serum levels in late stage cancer were shown to be the major cause of cancer-associated weight loss. MIC-1/GDF15 serum levels independently predict both atherosclerotic events and severity of rheumatoid arthritis (RA), suggesting serum levels are important in modifying disease expression. Controlling serum levels is the ratio of latent unprocessed MIC-1/GDF15 stromal stores to soluble mature MIC-1/GDF15 generated by the cell. Here, we investigate MIC-1/GDF15 secretion from U937 monocytoid cells and identify novel mechanisms designed to ensure secretion of unprocessed cytokine and creation of latent stromal stores. We find that endogenous MIC-1/GDF15 is secreted as both processed and unprocessed forms. Pulse chase analysis of MIC-1/GDF15 secretion reveals that unprocessed MIC-1/GDF15 precursor is rapidly secreted, while mature MIC-1/GDF15 generated within the cell by intracellular processing is secreted much slower, possibly via an alternate secretory route. The COOH-T 47 amino acids of the propeptide are responsible for rapid secretion of MIC-1/GDF15 precursor and this effect occurs in the trans-Golgi network (TGN)/post TGN compartment. Thus, variations in MIC-1/GDF15 intracellular processing, regulating the presence or absence of propeptide, are a powerful mechanism modulating rate of MIC-1/GDF15 secretion and proMIC-1/GDF15 stromal storage, with major impact on circulating levels of mature MIC-1/GDF15.