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标题：Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-inflammatory Effects through SHIP1/STAT3 Complexes
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作者：Thomas C. Chamberlain ; Sylvia T. Cheung ; Jeff S.J. Yoon 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：8
页码：1-31
DOI：10.1016/j.isci.2020.101433
语种：English
出版社：Elsevier
摘要：SummaryThe anti-inflammatory actions of interleukin-10 (IL10) are thought to be mediated primarily by the STAT3 transcription factor, but pro-inflammatory cytokines such as interleukin-6 (IL6) also act through STAT3. We now report that IL10, but not IL6 signaling, induces formation of a complex between STAT3 and the inositol polyphosphate-5-phosphatase SHIP1 in macrophages. Both SHIP1 and STAT3 translocate to the nucleus in macrophages. Remarkably, sesquiterpenes of the Pelorol family, which we previously described as allosteric activators of SHIP1 phosphatase activity, could induce SHIP1/STAT3 complex formation in cells and mimic the anti-inflammatory action of IL10 in a mouse model of colitis. Using crystallography and docking studies we identified a drug-binding pocket in SHIP1. Our studies reveal new mechanisms of action for both STAT3 and SHIP1 and provide a rationale for use of allosteric SHIP1-activating compounds, which mimic the beneficial anti-inflammatory actions of IL10.Video AbstractDisplay OmittedGraphical AbstractDisplay OmittedHighlights•Loss of normal interleukin-10 (IL10) function results in inflammatory diseases•IL10 or SHIP1 agonists induce formation of SHIP1/STAT3 complexes•SHIP1 Y190 phosphorylation is required for SHIP1/STAT3 complex formation•SHIP1 agonists mimic IL10 anti-inflammatory action in a mouse model of colitisMolecular Biology; Molecular Interaction; Immunity