Neuregulin-1β (NRG-1) is a membrane-bound or secreted growth and differentiation factor that mediates its action by binding to ErbB receptors. Circulating levels of NRG-1 are characterized by large inter-individual variability with the range of absolute values covering two orders of magnitude, from hundreds to tens of thousands of picograms per milliliter of blood. NRG-1 signaling via ErbB receptors contributes to the cell survival and downregulation of the inflammatory response. A higher level of circulating NRG-1 may indicate increased shedding of membrane-bound NRG-1, which in turn can contribute to better protection against cardiovascular stress or injury. However, it is unknown whether circulating NRG-1 can induce activation of ErbB receptors. In the current study, we performed an analysis of circulating NRG-1 functional activity using a cell-based ELISA measuring phosphorylation of ErbB3 induced by blood plasma obtained from healthy donors. We found high levels of ErbB3 activating activity in human plasma. No correlations were found between the levels of circulating NRG-1 and plasma ErbB3 activating activity. To determine the direct effect of circulating NRG-1, we incubated plasma with neutralizing antibody, which prevented the stimulatory effect of recombinant NRG-1 on activation of ErbB3. No effect of the neutralizing antibody was found on plasma-induced phosphorylation of ErbB3. We also found that a significant portion of circulating NRG-1 is comprised of full-length NRG-1 associated with large extracellular vesicles. Our results demonstrate that circulating NRG-1 does not contribute to plasma-induced ErbB3 activating activity and emphasizes the importance of functional testing of NRG-1 proteins in biological samples.

中文翻译：

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人血中的高ErbB3活化活性不是由于循环中的神经调节素1β引起的。

Neuregulin-1β（NRG-1）是膜结合或分泌的生长和分化因子，通过与ErbB受体结合而介导其作用。NRG-1的循环水平的特点是个体之间存在较大差异，其绝对值范围涵盖两个数量级，每毫升血液从数百皮克到数万皮克。通过ErbB受体的NRG-1信号传导有助于细胞存活和炎症反应的下调。循环中NRG-1含量较高可能表明与膜结合的NRG-1脱落增加，进而有助于更好地保护心血管疾病或伤害。但是，尚不清楚循环的NRG-1是否可以诱导ErbB受体的激活。在目前的研究中 我们使用基于细胞的ELISA测量了从健康供体获得的血浆诱导的ErbB3的磷酸化，从而进行了循环NRG-1功能活性的分析。我们发现人类血浆中高水平的ErbB3激活活性。在循环的NRG-1水平与血浆ErbB3活化活性之间未发现相关性。为了确定循环NRG-1的直接作用，我们将血浆与中和抗体一起孵育，这阻止了重组NRG-1对ErbB3激活的刺激作用。没有发现中和抗体对血浆诱导的ErbB3的磷酸化作用。我们还发现循环NRG-1的很大一部分由与大型细胞外囊泡相关的全长NRG-1组成。