IRAK4 kinase activity controls Toll-like receptor–induced inflammation through the transcription factor IRF5 in primary human monocytes
| Autor: | Aaron Winkler, Katherine L. Lee, Wouter Korver, Rachael Hawtin, Lih-Ling Lin, Margaret Fleming, Vikram R. Rao, Scott A. Jelinsky, Leah Cushing |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Active Transport Cell Nucleus Biochemistry Monocytes Proinflammatory cytokine 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Kinase activity Phosphorylation Protein kinase A Molecular Biology Transcription factor Protein Kinase Inhibitors Cells Cultured Toll-like receptor Chemistry Models Immunological NF-kappa B Computational Biology NF-kappa B p50 Subunit Cell Biology IRAK4 MAP Kinase Kinase Kinases Cell biology I-kappa B Kinase Enzyme Activation 030104 developmental biology Cytokine Interleukin-1 Receptor-Associated Kinases Gene Expression Regulation Toll-Like Receptor 7 Toll-Like Receptor 8 030220 oncology & carcinogenesis Interferon Regulatory Factors Cytokines Single-Cell Analysis Protein Processing Post-Translational Interferon regulatory factors Signal Transduction |
| Popis: | Interleukin-1 receptor–associated kinase 4 (IRAK4) plays a critical role in innate immune signaling by Toll-like receptors (TLRs), and loss of IRAK4 activity in mice and humans increases susceptibility to bacterial infections and causes defects in TLR and IL1 ligand sensing. However, the mechanism by which IRAK4 activity regulates the production of downstream inflammatory cytokines is unclear. Using transcriptomic and biochemical analyses of human monocytes treated with a highly potent and selective inhibitor of IRAK4, we show that IRAK4 kinase activity controls the activation of interferon regulatory factor 5 (IRF5), a transcription factor implicated in the pathogenesis of multiple autoimmune diseases. Following TLR7/8 stimulation by its agonist R848, chemical inhibition of IRAK4 abolished IRF5 translocation to the nucleus and thus prevented IRF5 binding to and activation of the promoters of inflammatory cytokines in human monocytes. We also found that IKKβ, an upstream IRF5 activator, is phosphorylated in response to the agonist-induced TLR signaling. Of note, IRAK4 inhibition blocked IKKβ phosphorylation but did not block the nuclear translocation of NFκB, which was surprising, given the canonical role of IKKβ in phosphorylating IκB to allow NFκB activation. Moreover, pharmacological inhibition of either IKKβ or the serine/threonine protein kinase TAK1 in monocytes blocked TLR-induced cytokine production and IRF5 translocation to the nucleus, but not nuclear translocation of NFκB. Taken together, our data suggest a mechanism by which IRAK4 activity regulates TAK1 and IKKβ activation, leading to the nuclear translocation of IRF5 and induction of inflammatory cytokines in human monocytes. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|