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

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 of the United States of America (2014-08-13)
Thomas B Sundberg, Hwan Geun Choi, Joo-Hye Song, Caitlin N Russell, Mahmud M Hussain, Daniel B Graham, Bernard Khor, John Gagnon, Daniel J O'Connell, Kavitha Narayan, Vlado Dančík, Jose R Perez, Hans-Christian Reinecker, Nathanael S Gray, Stuart L Schreiber, Ramnik J Xavier, Alykhan F Shamji
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Rat IL-10 ELISA Kit, for cell and tissue lysates
Sigma-Aldrich
Rat IL-10 ELISA Kit, for serum, plasma and cell culture supernatant
Sigma-Aldrich
Mouse IL-10 ELISA Kit, for serum, plasma and cell culture supernatant
Sigma-Aldrich
Human IL-10 ELISA Kit
Sigma-Aldrich
Human IL-10 R β ELISA Kit, for serum, plasma, cell culture supernatant and urine