Soluble mannose 6-phosphate/insulin-Like growth factor II (IGF-II) receptor inhibits interleukin-6-type cytokine-dependent proliferation by neutralization of IGF-II
Soluble mannose 6-phosphate/insulin-Like growth factor II (IGF-II) receptor inhibits interleukin-6-type cytokine-dependent proliferation by neutralization of IGF-II
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DOI：
10.1210/en.2003-0607
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发表时间：
2003-12-01
期刊：
影响因子：
4.8
通讯作者：
Blanchard, F
中科院分区：
文献类型：
--
作者：
Duplomb, L;Chaigne-Delalande, B;Blanchard, F
钙非依赖性甘露糖6-磷酸受体（CIMPR）是多种配体的受体，包括白血病抑制因子（LIF）、IL-6型细胞因子和IGF-II。CIMPR将新合成的配体靶向溶酶体并诱导分泌配体的内化/降解。CIMPR的天然可溶形式（sCIMPR）中和肝细胞和成纤维细胞上的IGF-II促有丝分裂效力。在此，我们表明sCIMPR也抑制LIF驱动的骨髓和淋巴细胞系的增殖。用IL-6和IL-11（不与CIMPR相互作用的另外两种IL-6型细胞因子）观察到类似的抑制。中和抗IGF-II抗体抑制IL-6、IL-11和LIF驱动的细胞增殖的程度与sCIMPR相同，表明sCIMPR中和血清IGF-II在IL-6型精氨酸依赖性细胞增殖中起主要作用。证实了这一观点，ERK 1/2和AKT/蛋白激酶B，细胞增殖和存活所必需的激酶，被IGF-II单独激活或被IL-6型细胞因子和IGF-II联合激活。单独的IL-6型细胞因子（高达10 ng/ml）不激活ERK 1/2或AKT，但激活STAT 3（信号转导和转录激活因子3），这是G1至S期细胞周期转换所必需的转录因子。因此，IGF-II激活ERK 1/2和AKT对于维持IL-6型细胞因子驱动的细胞扩增至关重要。
The calcium-independent mannose 6-phosphate receptor (CIMPR) is a receptor for multiple ligands, including leukemia inhibitory factor (LIF), an IL-6 type cytokine, and IGF-II. CIMPR targets newly synthesized ligands to lysosomes and induces internalization/degradation of secreted ligands. A natural soluble form of CIMPR (sCIMPR) neutralizes IGF-II mitogenic potency on hepatocytes and fibroblasts. Herein we show that sCIMPR also inhibits LIF-driven proliferation of myeloid and lymphoid cell lines. Similar inhibition was observed with IL-6 and IL-11, two other IL-6-type cytokines that do not interact with CIMPR. Neutralizing anti-IGF-II antibodies inhibited IL-6-, IL-11-, and LIF-driven cell proliferation to the same extent as sCIMPR, suggesting that neutralization of serum IGF-II by sCIMPR plays a major role in IL-6-type cytokine-dependent cell proliferation. Confirming this idea, ERK1/2 and AKT/protein kinase B, the kinases necessary for cell proliferation and survival, were activated by IGF-II alone or by the association of IL-6-type cytokines and IGF-II. IL-6-type cytokines alone (up to 10 ng/ml) did not activate ERK1/2 or AKT, but did activate STAT3 (signal transducer and activator of transcription 3), a transcription factor necessary for the G1 to S phase cell cycle transition. Activation of ERK1/2 and AKT by IGF-II thus appears essential to sustain cellular expansion driven by IL-6-type cytokines.