Ifn- Production by Tlr4-Stimulated Innate Immune Cells Is Negatively Regulated by Gsk3-

Wang, H.; Garcia, C.A.; Rehani, K.; Cekic, C.; Alard, P.; Kinane, D.F.; Mitchell, T.; Martin, M.

The Journal of Immunology 181(10): 6797-6802


DOI: 10.4049/jimmunol.181.10.6797
Accession: 068491055

Download citation:  

Article/Abstract emailed within 0-6 h
Payments are secure & encrypted
Powered by Stripe
Powered by PayPal

TLR 4 stimulation of innate immune cells induces a MyD88-independent signaling pathway that leads to the production of IFN-beta. In this study, we demonstrate glycogen synthase kinase 3-beta (GSK3-beta) plays a fundamental role in this process. Suppression of GSK3-beta activity by either pharmacological inhibition, small interfering RNA-mediated gene silencing, or ectopic expression of a kinase-dead GSK3-beta mutant enhanced IFN-beta production by TLR4-stimulated macrophages. Conversely, ectopic expression of a constitutively active GSK3-beta mutant severely attenuated IFN-beta production. GSK3-beta was found to negatively control the cellular levels of the transcription factor c-Jun and its nuclear association with ATF-2. Small interfering RNA-mediated knockdown of c-Jun levels abrogated the ability of GSK3-beta inhibition to augment IFN-beta, demonstrating that the ability of GSK3 to control IFN-beta production was due to its ability to regulate c-Jun levels. The ability of GSK3 inhibition to control IFN-beta production was confirmed in vivo as mice treated with a GSK3 inhibitor exhibited enhanced systemic levels of IFN-beta upon LPS challenge. These findings identify a novel regulatory pathway controlling IFN-beta production by TLR4-stimulated innate immune cells.