The MNK-1/eIF4E pathway as a new therapeutic pathway to target inflammation and remodelling in asthma

Autor: Michael Roth, Luigi Costa, Petra Seidel, Michael Tamm, Qingzhu Sun, Didier Lardinois
Rok vydání: 2016
Předmět:
Chemokine CCL11
0301 basic medicine
Eotaxin
RNA Stability
medicine.medical_treatment
Myocytes
Smooth Muscle
Active Transport
Cell Nucleus
Becaplermin
Down-Regulation
Inflammation
Protein Serine-Threonine Kinases
Biology
p38 Mitogen-Activated Protein Kinases
03 medical and health sciences
0302 clinical medicine
medicine
Humans
CXCL10
RNA
Messenger
Phosphorylation
RNA
Small Interfering
Protein kinase A
Cell Proliferation
Cell Nucleus
Aniline Compounds
Tumor Necrosis Factor-alpha
Intracellular Signaling Peptides and Proteins
NF-kappa B
Proto-Oncogene Proteins c-sis
Cell Biology
Asthma
Chemokine CXCL10
Kinetics
Eukaryotic Initiation Factor-4E
030104 developmental biology
Cytokine
030228 respiratory system
Purines
Chemokine secretion
Cancer research
Tumor necrosis factor alpha
Signal transduction
medicine.symptom
Signal Transduction
Zdroj: Cellular Signalling. 28:1555-1562
ISSN: 0898-6568
DOI: 10.1016/j.cellsig.2016.07.004
Popis: Therapeutic targets in asthma are reduction of airway inflammation and remodelling, the latter is not affected by available drugs. Here we present data that inhibition of MAPK-activated protein kinase (MNK)-1 reduces inflammation and remodelling. MNK-1 regulates protein expression by controlling mRNA stability, nuclear export and translation through the eukaryotic initiation factor 4E (eIF4E). Airway smooth muscle cells were derived from asthmatic and non-asthmatic donors. Cells were pre-treated with CGP57380 (MNK-1 inhibitor) or MNK-1 siRNA, before TNF-α stimulation. Cytokine and protein expression was analysed by ELISA, real time PCR and immunoblotting. Proliferation was monitored by cell counts. TNF-α activated MNK-1 phosphorylation between 15 and 30min. and subsequently eIF4E between 15 and 60min. EIF4E activity was inhibited by CGP57380 dose-dependently. Inhibition of MNK-1 by CGP57380 or MNK-1 siRNA significantly reduced TNF-α induced CXCL10 and eotaxin mRNA expression and secretion, but had no effect on IL-8. However, CXCL10 mRNA stability or NF-κB activity were not affected by MNK-1 inhibition. Furthermore, eIF4E was detected in the cytosol and the nucleus, but TNF-α did not affected its export from the nucleus. Cytokine array assessment showed that in addition to eotaxin and CXCL10, asthma relevant GRO α and RANTES were down-regulated by MNK-1 inhibition. In addition, MNK-1 inhibition significantly reduced FCS and PDGF-BB induced cell proliferation. We are the first to report that MNK-1 controls chemokine secretion and proliferation in human airway smooth muscle cells. Therefore we suggest that MNK-1 inhibition may present a new target to limit inflammation and remodelling in asthmatic airways.
Databáze: OpenAIRE
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