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

J Immunol. 2017 Feb 15;198(4):1638-1648. doi: 10.4049/jimmunol.1600467. Epub 2017 Jan 13.


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.

MeSH terms

  • Adenosine Triphosphatases / immunology
  • Adenosine Triphosphatases / metabolism*
  • Cation Transport Proteins / immunology
  • Cation Transport Proteins / metabolism*
  • Cells, Cultured
  • Copper-Transporting ATPases
  • Cytokines / biosynthesis
  • Cytokines / immunology
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Diaminopimelic Acid / pharmacology
  • Eukaryotic Initiation Factor-4E / metabolism*
  • Gene Expression Regulation*
  • Humans
  • Interleukin-1beta / biosynthesis
  • Interleukin-1beta / immunology
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / immunology
  • Macrophages / drug effects
  • Macrophages / immunology
  • NF-kappa B / metabolism
  • Nod1 Signaling Adaptor Protein / metabolism*
  • Signal Transduction* / drug effects
  • Toll-Like Receptor 4 / immunology
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Cation Transport Proteins
  • Cytokines
  • Eukaryotic Initiation Factor-4E
  • Interleukin-1beta
  • Interleukin-6
  • NF-kappa B
  • Nod1 Signaling Adaptor Protein
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Diaminopimelic Acid
  • p38 Mitogen-Activated Protein Kinases
  • Adenosine Triphosphatases
  • ATP7A protein, human
  • Copper-Transporting ATPases