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

被引：23

作者：

Chamberlain, Thomas C. ^{[1
,3
,4
]}

Cheung, Sylvia T. ^{[1
,3
,4
]}

Yoon, Jeff S. J. ^{[1
,3
,4
]}

Ming-Lum, Andrew ^{[1
,3
]}

Gardill, Bernd R. ^{[4
]}

Shakibakho, Soroush ^{[1
,3
]}

Dzananovic, Edis ^{[8
]}

Ban, Fuqiang ^{[6
]}

Samiea, Abrar ^{[1
,3
]}

Jawanda, Kamaldeep ^{[1
,3
]}

Priatel, John ^{[5
]}

Krystal, Gerald ^{[2
,5
]}

Ong, Christopher J. ^{[1
,3
,6
]}

Cherkasov, Artem ^{[6
]}

Andersen, Raymond J. ^{[7
]}

McKenna, Sean A. ^{[8
]}

Van Petegem, Filip ^{[4
]}

Mui, Alice L-F. ^{[1
,3
,4
]}

机构：

[1] Vancouver Coastal Hlth Res Inst, Immun & Infect Res Ctr, Vancouver, BC V6H 3Z6, Canada

[2] British Columbia Canc Res Ctr, Vancouver, BC V5Z 1L3, Canada

[3] Univ British Columbia, Dept Surg, Vancouver, BC, Canada

[4] Univ British Columbia, Dept Biochem & Mol Biol, Vancouver, BC, Canada

[5] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC, Canada

[6] Univ British Columbia, Dept Urol Sci, Vancouver, BC, Canada

[7] Univ British Columbia, Dept Chem, Vancouver, BC, Canada

[8] Univ Manitoba, Dept Chem, Winnipeg, MB, Canada

来源：

ISCIENCE | 2020年 / 23卷 / 08期

基金：

加拿大健康研究院; 加拿大自然科学与工程研究理事会;

关键词：

RATIONAL PROTEIN CRYSTALLIZATION; IL-10; FAMILY; INFLAMMATION; AQX-1125; COLITIS; MICE; PHOSPHATASE; CYTOKINES; EFFICACY; NETWORKS;

D O I：

10.1016/j.isci.2020.101433

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 poly-phosphate-5-phosphatase SHIP1 in macrophages. Both SHIP1 and STAT3 translo-cate to the nucleus in macrophages. Remarkably, sesquiterpenes of the Pelorol family, which we previously described as allosteric activators of SHIP1 phospha-tase activity, could induce SHIP1/STAT3 complex formation in cells and mimic the anti-inflammatory action of IL10 in a mouse model of colitis. Using crystallog-raphy 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.

引用

页数：31

共 22 条

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Noori, Shokoofe
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Daraei, Azam
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