title: The Role of the p38-MNK-eIF4E Signaling Axis in TNF Production Downstream of the NOD1 Receptor.
abstract: Activation of nucleotide-binding oligomerization domain (NOD) 1 and NOD2 by muropeptides triggers a complex transcriptional program in innate immune cells. However, little is known about posttranscriptional regulation of NOD1- and NOD2-dependent responses. When stimulated with a prototypic NOD1 agonist, N-acetylglucosaminyl-N-acetylmuramyl-l-alanyl-d-isoglutamyl-meso-diaminopimelic acid (GM-triDAP), human monocyte-derived macrophages (MDM) produced an order of magnitude more TNF, IL-6, and pro-IL-1β than did monocyte-derived dendritic cells (MDDC), despite similar NOD1 expression, similar cytokine mRNA kinetics, and comparable responses to LPS. TNF production by GM-triDAP-activated MDM was independent of autocrine IL-1. However, GM-triDAP-activated MDM translated TNF mRNA more efficiently than did MDDC. As an underlying mechanism, NOD1 triggering in MDM caused a more potent and long-lasting activation of the signaling axis involving p38 MAPK, MAPK-interacting kinase (MNK), and eukaryotic translation initiation factor 4E, which is a critical regulator of translation. Furthermore, MNK controlled TNF mRNA abundance in MDDC and MDM upon NOD1 triggering. NOD1-dependent responses were more sensitive to MNK inhibition than were TLR4-dependent responses. These results demonstrate the importance of the p38-MNK-eukaryotic translation initiation factor 4E axis in TNF production downstream of NOD1.
authors.affiliation: Laboratory of Clinical Immunology, National Research Center Institute of Immunology of the Federal Medical-Biological Agency, 115478 Moscow, Russia mvpashenkov@yandex.ru.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Pashenkov
authors.affiliation: Laboratory of Clinical Immunology, National Research Center Institute of Immunology of the Federal Medical-Biological Agency, 115478 Moscow, Russia.
authors.forename: Lyudmila S
authors.initials: LS
authors.lastname: Balyasova
authors.affiliation: Laboratory of Clinical Immunology, National Research Center Institute of Immunology of the Federal Medical-Biological Agency, 115478 Moscow, Russia.
authors.forename: Yulia A
authors.initials: YA
authors.lastname: Dagil
authors.affiliation: Laboratory of Clinical Immunology, National Research Center Institute of Immunology of the Federal Medical-Biological Agency, 115478 Moscow, Russia.
authors.forename: Boris V
authors.initials: BV
authors.lastname: Pinegin
mesh_terms: D000251:Adenosine Triphosphatases / Q000276:immunology / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D000073840:Copper-Transporting ATPases; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D003960:Diaminopimelic Acid / Q000494:pharmacology; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D016207:Cytokines; D039561:Eukaryotic Initiation Factor-4E; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D003960:Diaminopimelic Acid; D048051:p38 Mitogen-Activated Protein Kinases; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases