Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-inflammatory Effects through SHIP1/STAT3 Complexes
Thomas C. Chamberlain,
Sylvia T. Cheung,
Jeff S.J. Yoon,
Andrew Ming-Lum,
Bernd R. Gardill,
Soroush Shakibakho,
Edis Dzananovic,
Fuqiang Ban,
Abrar Samiea,
Kamaldeep Jawanda,
John Priatel,
Gerald Krystal,
Christopher J. Ong,
Artem Cherkasov,
Raymond J. Andersen,
Sean A. McKenna,
Filip Van Petegem,
Alice L-F. Mui
Affiliations
Thomas C. Chamberlain
Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada; Department of Surgery, University of British Columbia, Vancouver, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
Sylvia T. Cheung
Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada; Department of Surgery, University of British Columbia, Vancouver, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
Jeff S.J. Yoon
Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada; Department of Surgery, University of British Columbia, Vancouver, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
Andrew Ming-Lum
Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada; Department of Surgery, University of British Columbia, Vancouver, Canada
Bernd R. Gardill
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
Soroush Shakibakho
Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada; Department of Surgery, University of British Columbia, Vancouver, Canada
Edis Dzananovic
Department of Chemistry, University of Manitoba, Winnipeg, Canada
Fuqiang Ban
Department of Urological Sciences, University of British Columbia, Vancouver, Canada
Abrar Samiea
Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada; Department of Surgery, University of British Columbia, Vancouver, Canada
Kamaldeep Jawanda
Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada; Department of Surgery, University of British Columbia, Vancouver, Canada
John Priatel
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
Gerald Krystal
British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
Christopher J. Ong
Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada; Department of Surgery, University of British Columbia, Vancouver, Canada; Department of Urological Sciences, University of British Columbia, Vancouver, Canada
Artem Cherkasov
Department of Urological Sciences, University of British Columbia, Vancouver, Canada
Raymond J. Andersen
Department of Chemistry, University of British Columbia, Vancouver, Canada
Sean A. McKenna
Department of Chemistry, University of Manitoba, Winnipeg, Canada
Filip Van Petegem
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
Alice L-F. Mui
Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada; Department of Surgery, University of British Columbia, Vancouver, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada; Corresponding author
Summary: 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:
