@article{Chiu:2024,
author = {Chiu, C-Y and Willis-Owen, S and Wong, K and Farrow, S and Cookson, W and Moffatt, M and Zhang, Y},
journal = {Journal of Inflammation},
title = {MAP3K8 is a potential therapeutic target in airway epithelial inflammation},
url = {http://hdl.handle.net/10044/1/113071},
year = {2024}
}

Download

TY  - JOUR
AB  - Background: We 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 cells (NHBE) 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 and IL-8 levels by qPCRs and ELISAs.  We also examined potential small molecule inhibitors for MAP3K8 in the same models.  Results:  IL-1β significantly and consistently increased MAP3K8 expression after 2 hours in A549, BEAS-2B and NHBE cells.  Phosphorylation of MAP3K8 occurred at 20 minutes after IL-1β stimulation and MAP3K8 protein was degraded at 30 minutes. 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 minutes 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.Conclusions: These results confirm that MAP3K8 is a key mediator of the early inflammatory response and that it is a pote
AU  - Chiu,C-Y
AU  - Willis-Owen,S
AU  - Wong,K
AU  - Farrow,S
AU  - Cookson,W
AU  - Moffatt,M
AU  - Zhang,Y
PY  - 2024///
SN  - 1476-9255
TI  - MAP3K8 is a potential therapeutic target in airway epithelial inflammation
T2  - Journal of Inflammation
UR  - http://hdl.handle.net/10044/1/113071
ER  - 

Download