Sundberg, Thomas B.Choi, Hwan GeunSong, Joo-HyeRussell, Caitlin N.Hussain, Mahmud M.Graham, Daniel B.Khor, BernardGagnon, JohnO’Connell, Daniel J.Narayan, KavithaDančík, VladoPerez, Jose R.Reinecker, Hans-ChristianGray, Nathanael S.Schreiber, Stuart L.Xavier, Ramnik J.Shamji, Alykhan F.2019-10-032014Sundberg, 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.1412308111.0027-84240744-28311091-6490http://nrs.harvard.edu/urn-3:HUL.InstRepos:41461176Genetic 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.en-USJournal Article2019-10-0310.1073/pnas.1412308111