ArticleThe Journal of biological chemistry2017
IRAK4 kinase activity controls Toll-like receptor-induced inflammation through the transcription factor IRF5 in primary human monocytes.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 70 citations in OpenAlex.
- The Interleukin-1 Receptor-Associated Kinase 4 Inhibitor PF-06650833 Blocks Inflammation in Preclinical Models of Rheumatic Disease and in Humans Enrolled in a Randomized Clinical Trial.Arthritis & rheumatology (Hoboken, N.J.) · 2021Trial
- Inhibition of IRF5 hyperactivation protects from lupus onset and severity.The Journal of clinical investigation · 2020Trial
- Safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06650833, a selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, in single and multiple ascending dose randomized phase 1 studies in healthy subjects.Arthritis research & therapy · 2019Trial
- Contemporary design of small-molecule kinase modulators: orthosteric, allosteric and induced-proximity strategies.Nature reviews. Drug discovery · 2026Review
- Peripheral blood transcriptomic biomarkers for predicting antidepressant response in major depressive disorder.BMC psychiatry · 2026Article
- Reduced Methylation of IRF5 Gene as a Biomarker for Gestational Diabetes Mellitus.Medical science monitor : international medical journal of experimental and clinical research · 2025Article
- Interferon Regulator Factor 5: A Novel Inflammatory Marker and Promising Therapeutic Target in Ulcerative Colitis.Biomedicines · 2025Article
- Drug screen reveals new potent host-targeted antivirals against Mpox virus.Research square · 2025Article
- Drug screen reveals new potent host-targeted antivirals against Mpox virus.bioRxiv : the preprint server for biology · 2025Article
- Degradation of IRAK4 for the treatment of lipopolysaccharide-induced acute lung injury in mice.Frontiers in pharmacology · 2025Article
- IRAK4 Targeting: A Breakthrough Approach to Combat Hidradenitis Suppurativa.Biologics : targets & therapy · 2025Review
- Interferon regulatory factor 5: a potential target for therapeutic intervention in inflammatory diseases.Frontiers in immunology · 2025Review
- Article
- Metabolic changes in fibroblast-like synoviocytes in rheumatoid arthritis: state of the art review.Frontiers in immunology · 2024Review
- Brain rhythms control microglial response and cytokine expression via NF-κB signaling.Science advances · 2023Article
- IRAK1 inhibition blocks the HIV-1 RNA mediated pro-inflammatory cytokine response from microglia.The Journal of general virology · 2023Article
- Single-cell atlas of the human neonatal small intestine affected by necrotizing enterocolitis.PLoS biology · 2023Article
- The Response of Macrophages in Sepsis-Induced Acute Kidney Injury.Journal of clinical medicine · 2023Review
- Regulation of innate immune signaling by IRAK proteins.Frontiers in immunology · 2023Review
- CD163+ M2 Macrophages Promote Fibrosis in IgG4-Related Disease Via Toll-like Receptor 7/Interleukin-1 Receptor-Associated Kinase 4/NF-κB Signaling.Arthritis & rheumatology (Hoboken, N.J.) · 2022Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.