title: Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells.
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.
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142;
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Sundberg
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115;
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Joo-Hye
authors.initials: JH
authors.lastname: Song
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115;
authors.forename: Caitlin N
authors.initials: CN
authors.lastname: Russell
authors.affiliation: 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;
authors.forename: Mahmud M
authors.initials: MM
authors.lastname: Hussain
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142; and.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Graham
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Bernard
authors.initials: B
authors.lastname: Khor
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142; and.
authors.forename: John
authors.initials: J
authors.lastname: Gagnon
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142; and.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: O'Connell
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Kavitha
authors.initials: K
authors.lastname: Narayan
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142;
authors.forename: Vlado
authors.initials: V
authors.lastname: Dančík
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142;
authors.forename: Jose R
authors.initials: JR
authors.lastname: Perez
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Reinecker
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115;
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: 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.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: 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.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142; stuart_schreiber@harvard.edu xavier@molbio.mgh.harvard.edu ashamji@broadinstitute.org.
authors.forename: Alykhan F
authors.initials: AF
authors.lastname: Shamji
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D000069439:Dasatinib; D003713:Dendritic Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis*; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D009570:Nitriles / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D013844:Thiazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; C555318:CRTC3 protein, mouse; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; C577044:HG-9-91-01; C556062:IL10 protein, mouse; D018836:Inflammation Mediators; D009570:Nitriles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; D013844:Thiazoles; D014157:Transcription Factors; D016753:Interleukin-10; C471992:bosutinib; C474808:salt-inducible kinase-2, mouse; D017346:Protein Serine-Threonine Kinases; D000069439:Dasatinib
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