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| Status |
Public on Apr 27, 2021 |
| Title |
Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses in autoimmune disorders |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
High levels of inflammation are often present in autoimmune diseases and can impact the functioning of the immune system. Specifically, how surrounding inflammation affects cytokine responses has not been extensively studied. We use IL-6 and IL-27, two cytokines playing opposite roles in inflammation, to ask how cytokines adapt to the inflammatory environment. We show that IL-27 induces a more sustained STAT1 phosphorylation than IL-6, with the two cytokines inducing comparable levels of STAT3 phosphorylation. Mathematical and statistical modelling of IL-6 and IL-27 signaling identify STAT1 (or STAT3) binding dynamics to GP130 (or IL-27R) as the main parameter contributing to sustained pSTAT1 by IL-27. Mutation of Tyr613 on IL-27R decreased IL-27-induced STAT1 phosphorylation by 80%, with limited effect on STAT3 phosphorylation. The strong receptor/STAT coupling by IL-27 led to the induction of a unique gene expression program by this cytokine, which required sustained STAT1 phosphorylation and IRF1 expression and was enriched in classical Interferon Stimulated Genes. Interestingly, the STAT/receptor coupling exhibited by IL-6/IL-27 was altered in Crohn’s disease and SLE patients. IL-6/IL-27 induced a more potent STAT1 activation in SLE patients than in healthy controls, which can be explained by the higher STAT1 expression in these patients. Partial inhibition of JAK activation by sub-saturating doses of Tofacitinib lowered the levels of STAT1 activation by IL-6, representing a new strategy to treat auto-immune disorders where cytokine responses are dysregulated.
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| Overall design |
Human Th-1 cells were stimulated under 7 conditions each; control (unstimualted), IL-27 1h, IL-27 6h, IL-27 24h, HypIL-6 1h, HypIL-6 6h, HypIL-6 24h. Each condition has three biolocial replicates (human donors). IL-27 was used at 2nM and HypIL-6 was used at 10nM
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| Contributor(s) |
Wilmes S, Jeffrey P, Martinez-Fabregas J, Hafer M, Fyfe PK, Pohler E, Gaggero S, López-García M, Mitra S, Piehler J, Molina-París C, Moraga I |
| Citation(s) |
33871355 |
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| Submission date |
Jan 08, 2021 |
| Last update date |
Apr 27, 2021 |
| Contact name |
Stephan Wilmes |
| E-mail(s) |
swilmes@dundee.ac.uk
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| Organization name |
University of Dundee
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| Department |
School of Life Sciences
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| Lab |
Division of Cell Signalling and Immunology
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| Street address |
Dow Street
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| City |
Dundee |
| ZIP/Postal code |
DD1 5EH |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (21)
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| Relations |
| BioProject |
PRJNA690821 |
| SRA |
SRP300934 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE164479_RAW.tar |
30.3 Mb |
(http)(custom) |
TAR (of XLS) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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