dc.contributor.author | Sundberg, Thomas B. | |
dc.contributor.author | Choi, Hwan Geun | |
dc.contributor.author | Song, Joo-Hye | |
dc.contributor.author | Russell, Caitlin N. | |
dc.contributor.author | Hussain, Mahmud M. | |
dc.contributor.author | Graham, Daniel B. | |
dc.contributor.author | Khor, Bernard | |
dc.contributor.author | Gagnon, John | |
dc.contributor.author | O’Connell, Daniel J. | |
dc.contributor.author | Narayan, Kavitha | |
dc.contributor.author | Dančík, Vlado | |
dc.contributor.author | Perez, Jose R. | |
dc.contributor.author | Reinecker, Hans-Christian | |
dc.contributor.author | Gray, Nathanael S. | |
dc.contributor.author | Schreiber, Stuart L. | |
dc.contributor.author | Xavier, Ramnik J. | |
dc.contributor.author | Shamji, Alykhan F. | |
dc.date.accessioned | 2019-10-03T14:38:06Z | |
dc.date.issued | 2014 | |
dc.identifier.citation | Sundberg, T. B., H. G. Choi, J.-H. Song, C. N. Russell, M. M. Hussain, D. B. Graham, B. Khor, et al. 2014. “Small-Molecule Screening Identifies Inhibition of Salt-Inducible Kinases as a Therapeutic Strategy to Enhance Immunoregulatory Functions of Dendritic Cells.” Proceedings of the National Academy of Sciences 111 (34): 12468–73. https://doi.org/10.1073/pnas.1412308111. | |
dc.identifier.issn | 0027-8424 | |
dc.identifier.issn | 0744-2831 | |
dc.identifier.issn | 1091-6490 | |
dc.identifier.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:41461176 | * |
dc.description.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 (M Phi s) 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-MFs 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-1 beta, IL-6, IL-12, and TNF-alpha, and these coordinated effects are observed in human DCs-M Phi s and anti-inflammatory CD11c(+) CX(3)CR1(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. | |
dc.language.iso | en_US | |
dc.publisher | National Academy of Sciences | |
dash.license | LAA | |
dc.title | Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells | |
dc.type | Journal Article | |
dc.description.version | Version of Record | |
dc.relation.journal | Proceedings of the National Academy of Sciences of the United States of America | |
dash.depositing.author | Schreiber, Stuart L.::80f648d0514e642a8f97bb9b12b10db7::600 | |
dc.date.available | 2019-10-03T14:38:06Z | |
dash.workflow.comments | 1Science Serial ID 91221 | |
dc.identifier.doi | 10.1073/pnas.1412308111 | |
dash.source.volume | 111;34 | |
dash.source.page | 12468 | |