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

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    101 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

    • PROTEIN-KINASE INHIBITORS
    • NECROSIS-FACTOR-ALPHA
    • MAP KINASE
    • RHEUMATOID-ARTHRITIS
    • CONVERTING ENZYME
    • POTENTIAL ROLE
    • PATHWAY
    • PHOSPHORYLATION
    • INFLAMMATION
    • IDENTIFICATION

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