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

  • Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):12468-73. doi: 10.1073/pnas.1412308111.
Thomas B Sundberg  1 ,  Hwan Geun Choi  2 ,  Joo-Hye Song  3 ,  Caitlin N Russell  4 ,  Mahmud M Hussain  5 ,  Daniel B Graham  6 ,  Bernard Khor  7 ,  John Gagnon  6 ,  Daniel J O'Connell  6 ,  Kavitha Narayan  3 ,  Vlado Dančík  1 ,  Jose R Perez  1 ,  Hans-Christian Reinecker  3 ,  Nathanael S Gray  2 ,  Stuart L Schreiber  8 ,  Ramnik J Xavier  9 ,  Alykhan F Shamji  10
Affiliations
  • 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; [email protected] [email protected] [email protected].
  • 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 [email protected] [email protected] [email protected].
  • 10. Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142; [email protected] [email protected] [email protected].
PMID: 25114223 DOI: 10.1073/pnas.1412308111
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.

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