TY - JOUR T1 - Quantitative modeling of STAT1 and STAT3 dynamics in IFNγ and IL-10 pathways uncovered robustness of anti-inflammatory STAT3 signaling JF - bioRxiv DO - 10.1101/425868 SP - 425868 AU - U Sarma AU - M Maiti AU - S Bhadange AU - A Nair AU - A Srivastava AU - B Saha AU - D Mukherjee Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/01/16/425868.abstract N2 - Information relay by signal transduction pathways occasionally involves sharing of functionally opposing transcription factors. For instance, IFNγ-STAT1 and IL-10-STAT3 elicit pro and anti-inflammatory cellular responses, respectively, but IFNγ mediated STAT3 and IL-10 mediated STAT1 activation is also observed. Here, through experiments at the cell population level, we studied the dynamics of STAT1 and STAT3(S/1/3) in responses to both IFNγ and IL-10 stimulation and subsequently trained a simplified mathematical model that quantitatively explained the S/1/3 signal-response at different doses of IFNγ and IL-10. Next, to understand the robustness of the canonical signaling axis in each pathway, we simulated a costimulation scenario (IL-10 and IFNγ applied simultaneously) which predicted STAT3 activation would remain IL-10 driven in presence of IFNγ; subsequent experiments validated the same. We next investigated how protein expression variability may plausibly influence the robustness of IL-10-STAT3 signaling at the level of individual cells. Simulating thousands of single cells and analyzing their responses to co-stimulation we could identify emergence of two new subpopulations; in one subpopulation co-stimulation dominantly activated STAT3 and suppressed STAT1 activation, and, vice versa in the other subpopulation. Analyzing the protein concentration from these reciprocal subpopulations we found the key proteins whose cell-specific expression could control S/1/3 responses in individual cells. Taken together, we present a quantitative model that captures the signaling dynamics of STAT1 and STAT3 in response to functionally opposing cues and through single cell simulations show how reciprocal responses could emerge at the level of individual cells. ER -