A CSF-1 receptor kinase inhibitor targets effector functions and inhibits pro-inflammatory cytokine production from murine macrophage populations.
CSF-1 regulates macrophage differentiation, survival, and function, and is an attractive therapeutic target for chronic inflammation and malignant diseases. Here we describe the effects of a potent and selective inhibitor of CSF-1R-CYC10268-on CSF-1R-dependent signaling. In in vitro kinase assays, CYC10268 was active in the low nanomolar range and showed selectivity over other kinases such as Abl and Kit. CYC10268 blocked survival mediated by CSF-1R in primary murine bone marrow-derived macrophages (BMM) and in the factor-dependent cell line Ba/F3, in which the CSF-1R was ectopically expressed. CYC10268 also inhibited CSF-1 regulated signaling (Akt, ERK-1/2), gene expression (urokinase plasminogen activator, toll-like receptor 9, and apolipoprotein E), and priming of LPS-inducible cytokine production in BMM. In thioglycollate-elicited peritoneal macrophages (TEPM), which survive in the absence of exogenous CSF-1, CYC10268 impaired LPS-induced cytokine production and regulated expression of known CSF-1 target genes. These observations support the conclusion that TEPM are CSF-1 autocrine and that CSF-1 plays a central role in macrophage effector functions during inflammation. CSF-1R inhibitors such as CYC10268 provide a powerful tool to dissect the role of the CSF-1/CSF-1R signaling system in a range of biological systems and have potential for a number of therapeutic applications.
Irvine
Katharine M
KM
Cooperative Research Centre for Chronic Inflammatory Diseases and Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Burns
Christopher J
CJ
Wilks
Andrew F
AF
Su
Stephen
S
Hume
David A
DA
Sweet
Matthew J
MJ
D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D003001:Cloning, Molecular; D016207:Cytokines / Q000037:antagonists & inhibitors; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control*; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D051379:Mice; D050506:Mutant Chimeric Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010957:Plasmids; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D014162:Transfection
D016207:Cytokines; D050506:Mutant Chimeric Proteins; D016173:Macrophage Colony-Stimulating Factor; D020794:Receptor Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor