炎症介导的细胞因子反应在许多与血管生成相关的疾病的发展中至关重要。以血管生成为突出策略在许多情况下（如心血管疾病和癌症）显示出有限的效果。失败的原因之一可能是炎症与血管生成之间的相互依赖关系。炎症治疗主要以靶向性细胞因子如白细胞介素-6（IL-6）为目标，作用于T细胞、巨噬细胞、癌细胞和肌细胞，对这些细胞如何作用于内皮细胞的机制了解有限。因此，我们关注其中一个主要的炎症细胞因子，IL-6，在内皮细胞中介导的细胞内信号传导，通过构建详细的计算模型来量化评估。我们的模型定量地表征了IL-6经典信号传导和跨膜信号传导在激活信号转导与转录激活因子3 (STAT3)、磷脂酰肌醇3激酶/蛋白激酶B (PI3K/Akt) 和丝裂原活化蛋白激酶（MAPK）信号转导中的效应，分别磷酸化STAT3、细胞外调控激酶（ERK）和Akt。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STAT3(pSTAT3)、Akt(pAkt)和ERK(pERK)对IL-6经典信号传导和/或跨膜信号传导的动力学响应。模型预测，IL-6经典信号传导和跨膜信号传导诱导的反应依赖于IL-6和可溶性IL-6受体（sIL-6R）的剂量。此外，IL-6经典信号传导和跨膜信号传导在诱导下游信号中显示出类似的效能，然而，跨膜信号传导引起更强的下游反应，并在整体上对IL-6的效果起主导作用，这是由于体外实验条件中可溶性IL-6受体充足。此外，IL-6和sIL-6R水平都调节信号的强度。此外，我们的模型确定了具体调节下游炎症和/或血管生成信号（pSTAT3、pAkt和pERK）的有影响的物种和动力学参数。总的来说，该模型量化预测了IL-6经典信号传导和/或跨膜信号传导刺激的效应，并提供了分析和整合实验数据的框架。从更广泛的角度来看，该模型可用于识别在内皮细胞中影响IL-6介导的信号传导的潜在靶点，并量化研究它们对STAT3、Akt和ERK活化的影响。© 2023 Springer Nature Limited.

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 cardiovascular diseases 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, and 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 ERK (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 classic and trans-signaling showed similar potency in inducing downstream signaling; however, trans-signaling induces stronger downstream responses and plays a dominant role in the overall effects from IL-6 due to the in vitro experimental setting of abundant sIL-6R. 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 downstream inflammatory and/or angiogenic signals, pSTAT3, pAkt, and pERK responses. 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 potential targets that influence IL-6 mediated signaling in endothelial cells and to study their effects quantitatively in modulating STAT3, Akt, and ERK activation.© 2023. Springer Nature Limited.