Interleukin-6 is required for Neuregulin-1 induced HER2 signaling in lung epithelium.
Interleukin-6 is required for Neuregulin-1 induced HER2 signaling in lung epithelium.
复制标题
Neuregulin-1 诱导肺上皮中的 HER2 信号转导需要 Interleukin-6。
DOI：
10.1016/j.bbrc.2019.04.070
复制
发表时间：
2019
影响因子：
3.1
通讯作者：
Kern,JeffreyA
中科院分区：
文献类型：
--
作者：
Mishra,Rangnath;Foster,DanielG;Finigan,JamesH;Kern,JeffreyA
明确了解肺泡上皮屏障的调节机制对于开发新的治疗策略以减轻肺损伤至关重要。HER 2/HER 3受体酪氨酸激酶复合物在维持肺泡-毛细血管屏障中起核心作用。这种受体复合物被其配体神经调节蛋白-1（NRG-1）激活。还已知白细胞介素-6（IL-6）通过IL-6受体（IL-6 R）复合物的HER 2转磷酸化诱导HER 2信号传导（1）。由于这种相互作用，我们假设NRG-1和IL-6协同相互作用以激活HER 2/HER 3复合物。在培养的肺上皮细胞中进行研究，通过蛋白质印迹和共聚焦显微镜测量HER 2/IL-6/IL-6 R/GP 130相互作用和受体激活，通过ELISA测量IL-6产生，以及使用特异性抗体测量IL-6抑制，我们发现IL-6是NRG-1诱导的肺上皮细胞中HER 2活化所必需的。IL-6抑制导致NRG-1诱导的HER 2活化减少。IL-6 R和GP 130（IL-6 R复合物的亚基）与HER 2物理相关，并且是NRG-1诱导的HER 2活化所需的。IL-6受体的β亚基抑制GP 130，使NRG-1诱导的HER 2活化降低38%，低于对照组。最后，HER 2活化使IL-6分泌增加两倍以上，超过静息细胞（526 ± 131 vs 231 ± 39.7 pg/ml），抑制HER 2基因表达可使基础IL-6分泌减少80%以上这些发现确定了需要IL-6和IL-6 R复合物以允许NRG-1介导的HER 2活化，以及HER 2驱动的IL-6产生反馈环。
A clear understanding of the mechanisms that regulate the alveolar epithelium's barrier is critical to develop new therapeutic strategies to mitigate lung injury. The HER2/HER3 receptor tyrosine kinase complex plays a central role in maintaining the alveolar-capillary barrier. This receptor complex is activated by its ligand, neuregulin-1 (NRG-1). Interleukin-6 (IL-6) is also known to induce HER2 signaling through HER2 transphosphorylation by the IL-6 receptor (IL-6R) complex (1). Due to this interaction, we hypothesized that NRG-1 and IL-6 cooperatively interacted to activate the HER2/HER3 complex.Studies were performed in cultured pulmonary epithelial cells measuring the HER2/IL-6/IL-6R/GP130 interaction and receptor activation by western blotting and confocal microscopy, IL-6 production by ELISA, and IL-6 inhibition using specific antibodies, small molecule inhibitors and shRNA.We found that IL-6 was required for NRG-1 induced activation of HER2 in pulmonary epithelial cells. IL-6 inhibition led to a decrease in NRG-1 induced HER2 activation. The IL-6R and GP130, a subunit of the IL-6R complex, were physically associated with HER2 and were required for NRG-1 induced HER2 activation. Inhibition of GP130, the β-subunit of the IL-6 receptor decreased NRG-1 induced HER2 activation lower than control by 38% Finally, HER2 activation increased IL-6 secretion more than two-fold over resting cells (526 ± 131 vs 231 ± 39.7 pg/ml), and inhibition of HER2 gene expression decreased basal IL-6 secretion over 80% (89 + 4.6 vs 1.3 + 0.8 pg/ml).These findings identify a requirement for IL-6 and the IL-6R complex to allow NRG-1 mediated HER2 activation, and a HER2 driven IL-6 production feedback loop.