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The MNK-1/eIF4E pathway as a new therapeutic pathway to target inflammation and remodelling in asthma
Journal
Cellular Signalling
Volume
28
Number
10
Pages / Article-Number
1555-1562
Keywords
Asmc; Asthma; Cgp57380; Mnk-1; eIF4E
Abstract
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-alpha stimulation. Cytokine and protein expression was analysed by ELISA, real time PCR and immunoblotting. Proliferation was monitored by cell counts. TNF-alpha 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-alpha induced CXCL10 and eotaxin mRNA expression and secretion, but had no effect on IL-8. However, CXCL10 mRNA stability or NF-kappaB activity were not affected by MNK-1 inhibition. Furthermore, eIF4E was detected in the cytosol and the nucleus, but TNF-alpha did not affected its export from the nucleus. Cytokine array assessment showed that in addition to eotaxin and CXCL10, asthma relevant GRO alpha 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.
