Song Min, Wang Youli, Annex Brian H, Popel Aleksander S
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205.
Department of Medicine, Augusta University Medical College of Georgia, Augusta, Georgia, USA 30912.
bioRxiv. 2023 Feb 3:2023.02.03.526721. doi: 10.1101/2023.02.03.526721.
Inflammatory cytokine mediated responses are important in the development of many diseases that are associated with angiogenesis. Targeting angiogenesis as a prominent strategy has shown limited effects in many contexts such as peripheral arterial disease (PAD) and cancer. One potential reason for the unsuccessful outcome is the mutual dependent role between inflammation and angiogenesis. Inflammation-based therapies primarily target inflammatory cytokines such as interleukin-6 (IL-6) in T cells, macrophages, cancer cells, muscle cells, and there is a limited understanding of how these cytokines act on endothelial cells. Thus, we focus on one of the major inflammatory cytokines, IL-6, mediated intracellular signaling in endothelial cells by developing a detailed computational model. Our model quantitatively characterized the effects of IL-6 classic and trans-signaling in activating the signal transducer and activator of transcription 3 (STAT3), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) signaling to phosphorylate STAT3, extracellular regulated kinase (ERK) and Akt, respectively. We applied the trained and validated experiment-based computational model to characterize the dynamics of phosphorylated STAT3 (pSTAT3), Akt (pAkt), and extracellular regulated kinase (pERK) in response to IL-6 classic and/or trans-signaling. The model predicts that IL-6 classic and trans-signaling induced responses are IL-6 and soluble IL-6 receptor (sIL-6R) dose-dependent. Also, IL-6 trans-signaling induces stronger downstream signaling and plays a dominant role in the overall effects from IL-6. In addition, both IL-6 and sIL-6R levels regulate signaling strength. Moreover, our model identifies the influential species and kinetic parameters that specifically modulate the pSTAT3, pAkt, and pERK responses, which represent potential targets for inflammatory cytokine mediated signaling and angiogenesis-based therapies. Overall, the model predicts the effects of IL-6 classic and/or trans-signaling stimulation quantitatively and provides a framework for analyzing and integrating experimental data. More broadly, this model can be utilized to identify targets that influence inflammatory cytokine mediated signaling in endothelial cells and to study the effects of angiogenesis- and inflammation-based therapies.
炎症细胞因子介导的反应在许多与血管生成相关的疾病发展中起着重要作用。将血管生成作为一种突出的策略，在许多情况下如外周动脉疾病（PAD）和癌症中显示出有限的效果。治疗结果不理想的一个潜在原因是炎症与血管生成之间相互依赖的作用。基于炎症的疗法主要针对T细胞、巨噬细胞、癌细胞、肌肉细胞中的炎性细胞因子，如白细胞介素-6（IL-6），而对于这些细胞因子如何作用于内皮细胞的了解有限。因此，我们通过建立一个详细的计算模型，专注于主要炎性细胞因子之一IL-6介导的内皮细胞内信号传导。我们的模型定量表征了IL-6经典信号传导和转信号传导在激活信号转导和转录激活因子3（STAT3）、磷脂酰肌醇3激酶/蛋白激酶B（PI3K/Akt）以及丝裂原活化蛋白激酶（MAPK）信号传导方面的作用，这些信号传导分别使STAT3、细胞外调节激酶（ERK）和Akt磷酸化。我们应用经过训练和验证的基于实验的计算模型来表征磷酸化的STAT3（pSTAT3）、Akt（pAkt）和细胞外调节激酶（pERK）对IL-6经典信号传导和/或转信号传导的响应动力学。该模型预测，IL-6经典信号传导和转信号传导诱导的反应是IL-6和可溶性IL-6受体（sIL-6R）剂量依赖性的。此外，IL-6转信号传导诱导更强的下游信号传导，并在IL-6的整体效应中起主导作用。另外，IL-6和sIL-6R水平均调节信号传导强度。而且，我们的模型确定了特异性调节pSTAT3、pAkt和pERK反应的有影响的物种和动力学参数，这些代表了炎性细胞因子介导的信号传导和基于血管生成的疗法的潜在靶点。总体而言，该模型定量预测了IL-6经典信号传导和/或转信号传导刺激的效果，并提供了一个分析和整合实验数据的框架。更广泛地说，该模型可用于识别影响内皮细胞中炎性细胞因子介导的信号传导的靶点，并研究基于血管生成和炎症的疗法的效果。
