Mechanistic pathway modeling reveals how IL-10 generates pleiotropic immune responses

IL-10 is a key anti-inflammatory cytokine whose activity is impaired in autoimmune diseases. However, IL-10 also promotes inflammation under certain conditions, limiting the efficacy of IL-10-based therapies. Because the principles underlying these opposing effects remain unclear, we developed a mathematical model of the IL-10 signaling pathway to understand how such pleiotropic responses arise. Considering that STAT3 signaling is buffered against changes in IL-10RB receptor affinity, we provide a minimal mechanistic explanation for IL-10 variants with anti-inflammatory or pro-inflammatory biased responses produced by an altered receptor affinity. By linking model-predicted pSTAT1 and pSTAT3 abundances with transcriptomic changes, we identified IL-10-responsive genes that are regulated at different pSTAT thresholds. This could explain how IL-10 elicits distinct downstream responses at different signaling strengths, and suggests that, depending on the required response, the affinity of IL10 for its receptors should not always be enhanced. Overall, our study highlights how modeling can help disentangle IL-10 pleiotropy to support the rational development of more effective IL-10-based therapies.