Experiment-based Computational Model Predicts that IL-6 Trans-Signaling Plays a Dominant Role in IL-6 mediated signaling in Endothelial Cells.

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.