title: The MNK-1/eIF4E pathway as a new therapeutic pathway to target inflammation and remodelling in asthma.
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-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.
authors.affiliation: Pulmonary Cell Research, Department Biomedicine, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Seidel
authors.affiliation: Pulmonary Cell Research, Department Biomedicine, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland; Department of Biochemistry and Molecular Biology, School of Basic Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China.
authors.forename: Qingzhu
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Pulmonary Cell Research, Department Biomedicine, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Costa
authors.affiliation: Thoracic Surgery, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
authors.forename: Didier
authors.initials: D
authors.lastname: Lardinois
authors.affiliation: Pulmonary Cell Research, Department Biomedicine, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland; Pneumology Clinic, Internal Medicine, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Tamm
authors.affiliation: Pulmonary Cell Research, Department Biomedicine, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland; Pneumology Clinic, Internal Medicine, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. Electronic address: michael.roth@usb.ch.
authors.forename: Michael
authors.initials: M
authors.lastname: Roth
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000814:Aniline Compounds / Q000494:pharmacology; D001249:Asthma / Q000378:metabolism* / Q000473:pathology*; D000077214:Becaplermin; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D054413:Chemokine CCL11 / Q000235:genetics / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007700:Kinetics; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; C515456:CCL11 protein, human; C466997:CGP 57380; C114753:CXCL10 protein, human; D054413:Chemokine CCL11; D054357:Chemokine CXCL10; D039561:Eukaryotic Initiation Factor-4E; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D020574:Proto-Oncogene Proteins c-sis; D011687:Purines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D000077214:Becaplermin; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: ASMC; Asthma; CGP57380; MNK-1; eIF4E