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Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-inflammatory Effects through SHIP1/STAT3 Complexes

The 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 STA...

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Autores principales: Chamberlain, Thomas C., Cheung, Sylvia T., Yoon, Jeff S.J., Ming-Lum, Andrew, Gardill, Bernd R., Shakibakho, Soroush, Dzananovic, Edis, Ban, Fuqiang, Samiea, Abrar, Jawanda, Kamaldeep, Priatel, John, Krystal, Gerald, Ong, Christopher J., Cherkasov, Artem, Andersen, Raymond J., McKenna, Sean A., Van Petegem, Filip, Mui, Alice L-F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452241/
https://www.ncbi.nlm.nih.gov/pubmed/32823063
http://dx.doi.org/10.1016/j.isci.2020.101433
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author Chamberlain, Thomas C.
Cheung, Sylvia T.
Yoon, Jeff S.J.
Ming-Lum, Andrew
Gardill, Bernd R.
Shakibakho, Soroush
Dzananovic, Edis
Ban, Fuqiang
Samiea, Abrar
Jawanda, Kamaldeep
Priatel, John
Krystal, Gerald
Ong, Christopher J.
Cherkasov, Artem
Andersen, Raymond J.
McKenna, Sean A.
Van Petegem, Filip
Mui, Alice L-F.
author_facet Chamberlain, Thomas C.
Cheung, Sylvia T.
Yoon, Jeff S.J.
Ming-Lum, Andrew
Gardill, Bernd R.
Shakibakho, Soroush
Dzananovic, Edis
Ban, Fuqiang
Samiea, Abrar
Jawanda, Kamaldeep
Priatel, John
Krystal, Gerald
Ong, Christopher J.
Cherkasov, Artem
Andersen, Raymond J.
McKenna, Sean A.
Van Petegem, Filip
Mui, Alice L-F.
author_sort Chamberlain, Thomas C.
collection PubMed
description The 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 ABSTRACT:
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spelling pubmed-74522412020-09-03 Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-inflammatory Effects through SHIP1/STAT3 Complexes Chamberlain, Thomas C. Cheung, Sylvia T. Yoon, Jeff S.J. Ming-Lum, Andrew Gardill, Bernd R. Shakibakho, Soroush Dzananovic, Edis Ban, Fuqiang Samiea, Abrar Jawanda, Kamaldeep Priatel, John Krystal, Gerald Ong, Christopher J. Cherkasov, Artem Andersen, Raymond J. McKenna, Sean A. Van Petegem, Filip Mui, Alice L-F. iScience Article The 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 ABSTRACT: Elsevier 2020-08-02 /pmc/articles/PMC7452241/ /pubmed/32823063 http://dx.doi.org/10.1016/j.isci.2020.101433 Text en Crown Copyright © 2020. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Chamberlain, Thomas C.
Cheung, Sylvia T.
Yoon, Jeff S.J.
Ming-Lum, Andrew
Gardill, Bernd R.
Shakibakho, Soroush
Dzananovic, Edis
Ban, Fuqiang
Samiea, Abrar
Jawanda, Kamaldeep
Priatel, John
Krystal, Gerald
Ong, Christopher J.
Cherkasov, Artem
Andersen, Raymond J.
McKenna, Sean A.
Van Petegem, Filip
Mui, Alice L-F.
Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-inflammatory Effects through SHIP1/STAT3 Complexes
title Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-inflammatory Effects through SHIP1/STAT3 Complexes
title_full Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-inflammatory Effects through SHIP1/STAT3 Complexes
title_fullStr Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-inflammatory Effects through SHIP1/STAT3 Complexes
title_full_unstemmed Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-inflammatory Effects through SHIP1/STAT3 Complexes
title_short Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-inflammatory Effects through SHIP1/STAT3 Complexes
title_sort interleukin-10 and small molecule ship1 allosteric regulators trigger anti-inflammatory effects through ship1/stat3 complexes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452241/
https://www.ncbi.nlm.nih.gov/pubmed/32823063
http://dx.doi.org/10.1016/j.isci.2020.101433
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