ArticleJournal of inflammation (London, England)2024
MAP3K8 is a potential therapeutic target in airway epithelial inflammation.
Article in Journal of inflammation (London, England), 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Modulation of Pepsin-Mediated Inflammatory Responses in Vocal Cord Epithelial Cells by Amprenavir.The Laryngoscope · 2026Article
- HDAC1 dysregulation promotes pro-inflammatory microglial activation and aggravates post-stroke neuroinflammation.Annals of medicine · 2025Article
- Whole Genome Resequencing Reveals the Genetic Basis of Desert Arid Climate Adaptation in Lop Sheep.Animals : an open access journal from MDPI · 2025Article
- Dexmedetomidine Blocks the ERK Pathway by Inhibiting MAP3K8 to Achieve a Protective Effect in Lung Ischemia/Reperfusion Injury.The Kaohsiung journal of medical sciences · 2025Article
- Multi-Layered Analysis of TGF-β Signaling and Regulation via DNA Methylation and microRNAs in Astrocytic Tumors.International journal of molecular sciences · 2025Article
- Analysis of the Expression Patterns of Tumor Necrosis Factor Alpha Signaling Pathways and Regulatory MicroRNAs in Astrocytic Tumors.International journal of molecular sciences · 2025Article
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Authors and funding
7 authors.
Funding
Abstract
backgroundWe have previously discovered clusters of sequentially negative and positive modulators of acute inflammation during cytokine stimulation in epithelial cells and identified potential targets for therapy within these clusters. MAP3K8 is a druggable kinase that we found to be a hub of a principal interaction network. We describe here the results of MAP3K8 knockdown in the A549 lung cancer cell line, the BEAS-2B epithelial cell line and normal human bronchial epithelial (NHBE) cells following IL-1β stimulation. We analysed signalling transduction and global gene expression after IL-1β stimulation with and without MAP3K8 knockdown, quantifying levels of the inflammatory cytokines IL-6, IL-8 and RANTES levels by qPCRs and/or by ELISAs. We also examined potential small molecule inhibitors for MAP3K8 in the same models.
resultsIL-1β significantly and consistently increased MAP3K8 expression after 2 h in A549, BEAS-2B and NHBE cells. Phosphorylation of MAP3K8 occurred at 20 min after IL-1β stimulation and MAP3K8 protein was degraded at 30 min. MAP3K8 knockdown significantly reduced IL-6, IL-8 levels after IL-1β stimulation and yielded a 10-fold enhancement of the anti-inflammatory effects of dexamethasone. Phosphorylation of ERK1/2 (P-ERK1/2) and phosphorylation of SAPK/JNK (P-SAPK/JNK) decreased at 30 min after IL-1β stimulation with MAP3K8 knockdown. The combination of dexamethasone and MAP3K8 knockdown resulted in greater inhibition of phosphorylated ERK1/2 and SAPK/JNK. Nineteen genes including MMP1, MMP3, MMP10, ITGB8, LAMC2 and PLAT (P corrected < 0.01 respectively) demonstrated a distinct altered temporal response to IL-1β following suppression of MAP3K8. However, putative MAP3K8 inhibitors including Tpl2-1, Tpl2-2 and GSK2222867A only showed inhibition of IL-6 and IL-8 production at a high dose.
conclusionsThese results confirm that MAP3K8 is a key mediator of the early inflammatory response and that it is a potential target in inflammatory diseases. However, current tool compounds do not effectively inhibit its effects.
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