The Role of the p38-MNK-eIF4E Signaling Axis in TNF Production Downstream of the NOD1 Receptor

• Published in: The Journal of immunology (1950) 2017-02, Vol.198 (4), p.1638-1648
• Main Authors: Pashenkov, Mikhail V, Balyasova, Lyudmila S, Dagil, Yulia A, Pinegin, Boris V
• Format: Article
• Language: English
• Subjects: Activation; Adenosine Triphosphatases - immunology; Adenosine Triphosphatases - metabolism; Autocrine signalling; Cation Transport Proteins - immunology; Cation Transport Proteins - metabolism; Cells, Cultured; Copper-transporting ATPases; Cytokines - biosynthesis; Cytokines - immunology; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Diaminopimelic Acid - pharmacology; Eukaryotic Initiation Factor-4E - metabolism; Gene expression; Gene Expression Regulation; Humans; Initiation factor eIF-4E; Interleukin 1; Interleukin 6; Interleukin-1beta - biosynthesis; Interleukin-1beta - immunology; Interleukin-6 - biosynthesis; Interleukin-6 - immunology; Kinetics; Lipopolysaccharides; Macrophages; Macrophages - drug effects; Macrophages - immunology; MAP kinase; Monocytes; NF-kappa B - metabolism; Nod1 protein; Nod1 Signaling Adaptor Protein - metabolism; NOD2 protein; Oligomerization; p38 Mitogen-Activated Protein Kinases - metabolism; Post-transcription; Receptor mechanisms; Signal Transduction - drug effects; TLR4 protein; Toll-Like Receptor 4 - immunology; Toll-like receptors; Tumor necrosis factor; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1600467

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.