Unknown

Dataset Information

0

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 (M?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-M?s 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?, IL-6, IL-12, and TNF-?, and these coordinated effects are observed in human DCs-M?s 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.

SUBMITTER: Sundberg TB 

PROVIDER: S-EPMC4151730 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Sundberg Thomas B TB   Choi Hwan Geun HG   Song Joo-Hye JH   Russell Caitlin N CN   Hussain Mahmud M MM   Graham Daniel B DB   Khor Bernard B   Gagnon John J   O'Connell Daniel J DJ   Narayan Kavitha K   Dančík Vlado V   Perez Jose R JR   Reinecker Hans-Christian HC   Gray Nathanael S NS   Schreiber Stuart L SL   Xavier Ramnik J RJ   Shamji Alykhan F AF  

Proceedings of the National Academy of Sciences of the United States of America 20140811 34


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 li  ...[more]

Similar Datasets

| S-EPMC10546379 | biostudies-literature
| S-EPMC5626034 | biostudies-literature
| S-EPMC8057676 | biostudies-literature
| S-EPMC6976658 | biostudies-literature
| S-EPMC3749438 | biostudies-literature
| S-EPMC7295197 | biostudies-literature
| S-EPMC7133458 | biostudies-literature
| S-EPMC8566462 | biostudies-literature
| S-EPMC5856641 | biostudies-literature
| S-EPMC5702497 | biostudies-literature