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Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):12468-73. doi: 10.1073/pnas.1412308111. Epub 2014 Aug 11.

Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells.

Author information

1
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142;
2
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115;
3
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114;
4
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115;
5
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138; Howard Hughes Medical Institute, Cambridge, MA 02142;
6
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142; and.
7
Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114.
8
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138; Howard Hughes Medical Institute, Cambridge, MA 02142; stuart_schreiber@harvard.edu xavier@molbio.mgh.harvard.edu ashamji@broadinstitute.org.
9
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142; and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114 stuart_schreiber@harvard.edu xavier@molbio.mgh.harvard.edu ashamji@broadinstitute.org.
10
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142; stuart_schreiber@harvard.edu xavier@molbio.mgh.harvard.edu ashamji@broadinstitute.org.

Abstract

Genetic alterations that reduce the function of the immunoregulatory cytokine IL-10 contribute to colitis in mouse and man. Myeloid cells such as macrophages (MΦs) and dendritic cells (DCs) play an essential role in determining the relative abundance of IL-10 versus inflammatory cytokines in the gut. As such, using small molecules to boost IL-10 production by DCs-MΦs represents a promising approach to increase levels of this cytokine specifically in gut tissues. Toward this end, we screened a library of well-annotated kinase inhibitors for compounds that enhance production of IL-10 by murine bone-marrow-derived DCs stimulated with the yeast cell wall preparation zymosan. This approach identified a number of kinase inhibitors that robustly up-regulate IL-10 production including the Food and Drug Administration (FDA)-approved drugs dasatinib, bosutinib, and saracatinib that target ABL, SRC-family, and numerous other kinases. Correlating the kinase selectivity profiles of the active compounds with their effect on IL-10 production suggests that inhibition of salt-inducible kinases (SIKs) mediates the observed IL-10 increase. This was confirmed using the SIK-targeting inhibitor HG-9-91-01 and a series of structural analogs. The stimulatory effect of SIK inhibition on IL-10 is also associated with decreased production of the proinflammatory cytokines IL-1β, IL-6, IL-12, and TNF-α, and these coordinated effects are observed in human DCs-MΦs and anti-inflammatory CD11c(+) CX3CR1(hi) cells isolated from murine gut tissue. Collectively, these studies demonstrate that SIK inhibition promotes an anti-inflammatory phenotype in activated myeloid cells marked by robust IL-10 production and establish these effects as a previously unidentified activity associated with several FDA-approved multikinase inhibitors.

PMID:
25114223
PMCID:
PMC4151730
DOI:
10.1073/pnas.1412308111
[Indexed for MEDLINE]
Free PMC Article

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