title: Translational control of human neutrophil responses by MNK1.
abstract: A growing number of inflammatory and immune processes in vivo have been shown to be influenced by neutrophil-derived cytokines. Whereas the underlying transcriptional mechanisms are increasingly well understood, the translational regulation of this neutrophil response remains largely unexplored. Here, we show that the MNK1, which participates in translational control in several cell types, is activated in response to physiological neutrophil agonists (LPS, TNF-α) in the cytoplasmic and nuclear compartments. With the use of various pharmacological inhibitors, we found that MNK1 activation takes place downstream of the TAK1-p38 MAPK axis in neutrophils, whereas the MEK/ERK, JNK, PI3K, and PKC pathways are not involved. Pharmacological blockade of MNK1, as well as overexpression experiments, established that cytokine protein synthesis (but not gene expression) is under the control of MNK1 in neutrophils. Likewise, MNK1 inhibition reversed the antiapoptotic effect of LPS and TNF-α in neutrophils, and this was accompanied by a decreased expression of the antiapoptotic protein Mcl-1. Thus, MNK1 appears to be an important regulator of neutrophil responses. Although MNK1 inhibition did not affect protein recruitment to mRNA caps, it decreased the phosphorylation of molecules implicated in translation initiation control, such as S6K, S6, and hyperphosphorylated 4E-BP1. These molecular targets of MNK1 are shared with those of PI3K in neutrophils, and accordingly, MNK1 inhibition partially impaired the belated PI3K/Akt activation elicited by LPS or TNF in these cells. Given the importance of neutrophils and their products in numerous chronic inflammatory disorders, MNK1 could represent an attractive therapeutic target.
authors: 1.Pulmonary Division/Research, Université de Sherbrooke, 3001, 12e avenue Nord, pièce 4849 Sherbrooke, Québec, Canada J1H 5N4. patrick.mcdonald@usherbrooke.ca Twitter: http://pages.usherbrooke.ca./mcdonaldlab.
authors: Carl F
authors: CF
authors: Fortin
authors: Thomas Z
authors: TZ
authors: Mayer
authors: Alexandre
authors: A
authors: Cloutier
authors: Patrick P
authors: PP
authors: McDonald
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D016207:Cytokines / Q000096:biosynthesis; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004795:Enzyme Stability / Q000187:drug effects; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D012315:RNA Caps / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013347:Subcellular Fractions / Q000201:enzymology
chemical_list: D000814:Aniline Compounds; C466997:CGP 57380; D016207:Cytokines; D039561:Eukaryotic Initiation Factor-4E; D047908:Intracellular Signaling Peptides and Proteins; D011687:Purines; D012315:RNA Caps; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: apoptosis; cytokines; protein translation