Protein kinase C delta and eta isoenzymes control the shedding of the interleukin 6 receptor alpha in myeloma cells.
Protein kinase C delta and eta isoenzymes control the shedding of the interleukin 6 receptor alpha in myeloma cells.
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DOI：
10.1042/0264-6021:3580193
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发表时间：
2001-08
期刊：
影响因子：
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通讯作者：
W. Thabard;M. Collette;R. Bataille;M. Amiot
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文献类型：
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作者：
W. Thabard;M. Collette;R. Bataille;M. Amiot
可溶性白细胞介素6受体α是白细胞介素6（IL-6）的激动性分子，在多发性骨髓瘤的生物学中很重要。更确切地说，它增强了IL-6在肿瘤进展过程中的有害作用，促进了血管生成和骨吸收。由于多发性骨髓瘤中白细胞介素6受体α（IL-6 R α）脱落的机制尚不清楚，我们在XG-6人骨髓瘤细胞系中对其进行了研究。在这里，我们提供的证据表明，PMA诱导的IL-6 R α脱落是由金属蛋白酶和蛋白激酶C（PKC）同工酶，不需要Ca（2+）的激活控制。我们发现，XG-6细胞表达PKC-δ，-eta和-zeta同工酶。然而，在用PMA刺激后，只有PKC-δ和PKC-η被激活，如通过其易位到膜所示。PMA处理诱导其活性环中PKC-δ磷酸化的增加。此外，通过使用PKC-δ的特异性抑制剂rottlerin，我们证明PKC-δ参与PMA诱导的IL-6 R α脱落。通过使用丝裂原活化蛋白激酶（MAPK）通路的特异性抑制剂UO 126，我们发现PMA诱导的IL-6 R α脱落部分由MAPK通路介导。最后，而GF 109203 X，一种通用的PKC抑制剂，抑制ERK 1/2（细胞外信号调节蛋白激酶1/2）的激活，rottlerin没有抑制作用，表明Ras/MAPK激活是PKC依赖性的，但PKC-δ-独立。综上所述，这些结果表明PMA诱导的IL-6 R α脱落是由PKC同工酶网络介导的。
The soluble interleukin 6 receptor alpha is an agonistic molecule of interleukin 6 (IL-6) and is important in the biology of multiple myeloma. More precisely, it potentiates the deleterious effects of IL-6 during tumour progression, facilitating angiogenesis and bone resorption. Because the mechanisms involved in the shedding of the interleukin 6 receptor alpha (IL-6Ralpha) in multiple myeloma are not known, we have investigated them in the XG-6 human myeloma cell line. Here we provide evidence that PMA-induced IL-6Ralpha shedding is controlled by a metalloproteinase and by protein kinase C (PKC) isoenzymes that do not require Ca(2+) for their activation. We show that XG-6 cells express PKC-delta, -eta and -zeta isoenzymes. However, after stimulation with PMA, only PKC-delta and PKC-eta are activated, as shown by their translocation to the membrane. Treatment with PMA induces an increase in PKC-delta phosphorylation in its active loop. In addition, by using rottlerin, a specific inhibitor of PKC-delta, we demonstrate that PKC-delta is involved in the PMA-induced shedding of IL-6Ralpha. With the use of UO126, a specific inhibitor of the mitogen-activated protein kinase (MAPK) pathway, we show that the PMA-induced IL-6Ralpha shedding is mediated in part by the MAPK pathway. Finally, whereas GF109203X, a general PKC inhibitor, inhibits the activation of ERK1/2 (extracellular signal-regulated protein kinase 1/2), rottlerin has no inhibitory effect, indicating that the Ras/MAPK activation is PKC-dependent but PKC-delta-independent. Taken together, these results suggest that the PMA-induced shedding of IL-6Ralpha is mediated by a PKC isoenzyme network.