biostudies-literatureWilmes SUniversity of LeedsDFGHorizon 2020 Framework ProgrammeEMBONHLBI NIH HHSNational Heart, Lung, and Blood InstituteEPSRCWellcome TrustEngineering and Physical Sciences Research Councile66014https://www.ebi.ac.uk/biostudies/studies/S-EPMC8099432biostudies-literatureUnknown10Cytokines elicit pleiotropic and non-redundant activities despite strong overlap in their usage of receptors, JAKs and STATs molecules. We use IL-6 and IL-27 to ask how two cytokines activating the same signaling pathway have different biological roles. We found that IL-27 induces more sustained STAT1 phosphorylation than IL-6, with the two cytokines inducing comparable levels of STAT3 phosphorylation. Mathematical and statistical modeling of IL-6 and IL-27 signaling identified STAT3 binding to GP130, and STAT1 binding to IL-27Rα, as the main dynamical processes contributing to sustained pSTAT1 levels by IL-27. Mutation of Tyr613 on IL-27Rα decreased IL-27-induced STAT1 phosphorylation by 80% but had limited effect on STAT3 phosphorgylation. Strong receptor/STAT coupling by IL-27 initiatedeLifeCompetitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses.PMC8099432714680K22HL125593SFB 944, P8/Z454–2017K22 HL125593202323/Z/16/Z764698ERC-206-STG1969354Lopez-Garcia MMoraga IPiehler JLythe GMartinez-Fabregas JGaggero SGuerrier TLaunay DFyfe PKHafer MMolina-Paris CTaylor CWilmes SJeffrey PAPohler EMitra SfalseCompetitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses.Cytokines elicit pleiotropic and non-redundant activities despite strong overlap in their usage of receptors, JAKs and STATs molecules. We use IL-6 and IL-27 to ask how two cytokines activating the same signaling pathway have different biological roles. We found that IL-27 induces more sustained STAT1 phosphorylation than IL-6, with the two cytokines inducing comparable levels of STAT3 phosphorylation. Mathematical and statistical modeling of IL-6 and IL-27 signaling identified STAT3 binding to GP130, and STAT1 binding to IL-27Rα, as the main dynamical processes contributing to sustained pSTAT1 levels by IL-27. Mutation of Tyr613 on IL-27Rα decreased IL-27-induced STAT1 phosphorylation by 80% but had limited effect on STAT3 phosphorgylation. Strong receptor/STAT coupling by IL-27 initiated2021-01-01T00:00:00Z2021 Apr2026-05-10T02:48:44.383Z2022-02-10T14:04:36.524ZS-EPMC80994323387135510.7554/eLife.66014