TPL2-mediated activation of ERK1 and ERK2 regulates the processing of pre-TNF alpha in LPS-stimulated macrophages

Simon Rousseau, Matoula Papoutsopoulou, Antony Symons, Dorthe Cook, John M. Lucocq, Alan R. Prescott, Anne O' Garra, Steven C. Ley, Philip Cohen

Research output: Contribution to journalArticlepeer-review

106 Citations (Scopus)

Abstract

Activation of the TPL2-MKK1/2-ERK1/2 signalling pathway is essential for lipopolysaccharide (LPS)-stimulated production of TNF alpha in macrophages. Here, we demonstrate that, unexpectedly, TPL2-deficient or MKK1-inhibited macrophages produce near normal levels of pre-TNF alpha when TLR2, TLR4 and TLR6 are activated by their respective agonists, but fail to secrete TNF alpha. We show that LPS stimulates the appearance of pre-TNF alpha at the cell surface and that this is prevented by inhibition of MAPK kinases 1 and 2 (MKK1/2) or in TPL2-deficient macrophages. However, the transport of pre-TNF alpha from the Golgi to the plasma membrane is unaffected by inhibition of the TPL2-MKK1/2-ERK1/2 pathway. Finally, we show that TACE, the protease that cleaves pre-TNF alpha to secreted TNF alpha, is phosphorylated by ERK1 and ERK2 (ERK1/2) at Thr735 in LPS-stimulated macrophages. Therefore, although TACE activity per se is not required for the LPS-stimulated cell surface expression of pre-TNF alpha, the phosphorylation of this protease might contribute to, or be required for, the cell surface expression of the pre-TNF alpha-TACE complex.

Original languageEnglish
Pages (from-to)149-154
Number of pages6
JournalJournal of Cell Science
Volume121
Issue number2
DOIs
Publication statusPublished - 15 Jan 2008

Keywords

  • Animals
  • Cell Membrane
  • Gene Expression Regulation, Enzymologic
  • Golgi Apparatus
  • Humans
  • Lipopolysaccharides
  • MAP Kinase Kinase Kinases
  • MAP Kinase Signaling System
  • Macrophages
  • Mice
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Models, Biological
  • Proto-Oncogene Proteins
  • Tumor Necrosis Factor-alpha

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