A Multi-Scale Mechanistic Model of Ulcerative Colitis to Investigate the Effects of Selective Suppression of IL-6 Trans-Signaling

• Published in: Clinical and translational science Vol. 18; no. 9; p. e70366
• Main Authors: Sternebring, Ola, Patidar, Nikhil, Ravi, Arjun, Carcillo, Ruth, Rivollier, Aymeric, Wang, Zhongyu, Venkatapurapu, Sai Phanindra, Behar, Marcelo, Read, Simon, Szabady, Rose, Sørensen, Jørgen, D'Alessandro, Paul M, Pinton, Philippe
• Format: Journal Article
• Language: English
• Published: United States 01.09.2025
• Subjects: Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - immunology; Colitis, Ulcerative - metabolism; Colitis, Ulcerative - pathology; Computer Simulation; Cytokine Receptor gp130 - metabolism; Humans; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - metabolism; Models, Biological; Receptors, Interleukin-6 - antagonists & inhibitors; Receptors, Interleukin-6 - metabolism; Signal Transduction - drug effects; Signal Transduction - immunology; computational biology; gastrointestinal; multiscale modeling; mechanism‐based pharmacokinetics‐pharmacodynamics; inflammation; immunology
• ISSN: 1752-8062; 1752-8062
• DOI: 10.1111/cts.70366

Interleukin 6 (IL-6) has previously been identified as playing a role in ulcerative colitis (UC) by activating the signal-transducing element gp130 through ligation of either the membrane-bound or soluble IL-6 receptor (termed classic and trans-signaling respectively). It has been proposed that selective inhibition of trans-IL-6 signaling could ameliorate the deleterious, pro-inflammatory effects of IL-6, while preserving the homeostatic activity of classic IL-6 signaling. We developed an in silico, mechanistic model of UC in two stages to compare the biological effects that result from inhibition of classic and trans-IL-6 signaling. In the first stage, we developed a limited-scope model of IL-6 signaling to establish the quantitative properties of classic and trans-signaling pathways on a short timescale following stimulation with IL-6. The model included both a pan-inhibitor of IL-6 classic and trans-signaling and a soluble gp130-Fc that selectively inhibited trans-signaling. In the second stage, we developed a multi-scale model of UC to study the pharmacodynamic effects of cytokine signaling inhibition and optimize treatment regimens. Across three virtual experiments, both selective and global suppression of IL-6 signaling were associated with a transition away from an inflammatory state in patients with moderate to severe inflammatory activity. In our multi-scale model, we identified a dose-response relationship between selective inhibition of trans-IL-6 signaling and tissue regeneration. Moreover, selective inhibition of trans-IL-6 signaling effectively suppressed inflammation and induced faster gut tissue healing than global IL-6 suppression. These findings suggest that global suppression of IL-6 signaling could negatively affect IL-6-induced regeneration activity, whereas this effect is less likely for selective inhibition.