Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 49, Pages 17432-17437Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1418399111
Keywords
IKK beta; interferon beta; IRF5; plasmacytoid dendritic cell; TLR7
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Funding
- Wellcome Trust [WT100294]
- UK Medical Research Council
- AstraZeneca
- Boehringer Ingelheim
- GlaxoSmithKline
- Janssen Pharmaceutica
- Merck-Serono
- Pfizer
- Medical Research Council [MC_UU_12016/11, MR/K000985/1] Funding Source: researchfish
- MRC [MC_UU_12016/11, MR/K000985/1] Funding Source: UKRI
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The siRNA knockdown of IFN Regulatory Factor 5 (IRF5) in the human plasmacytoid dendritic cell line Gen2.2 prevented IFN alpha production induced by compound CL097, a ligand for Toll-like receptor 7 (TLR7). CL097 also stimulated the phosphorylation of IRF5 at Ser462 and stimulated the nuclear translocation of wild-type IRF5, but not the IRF5[Ser462Ala] mutant. The CL097-stimulated phosphorylation of IRF5 at Ser462 and its nuclear translocation was prevented by the pharmacological inhibition of protein kinase IKK beta or the siRNA knockdown of IKK beta or its upstream activator, the protein kinase TAK1. Similar results were obtained in a murine macrophage cell line stimulated with the TLR7 agonist compound R848 or the nucleotide oligomerization domain 1 (NOD1) agonist KF-1B. IKK beta phosphorylated IRF5 at Ser462 in vitro and induced the dimerization of wild-type IRF5 but not the IRF5[S462A] mutant. These findings demonstrate that IKK beta activates two master transcription factors of the innate immune system, IRF5 and NF-kappa B.
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