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First published online January 10, 2008
doi: 10.1242/10.1242/jcs.018671

Journal of Cell Science 121, 149-154 (2008)
Published by The Company of Biologists 2008
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Short Report

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

Simon Rousseau1,*, Matoula Papoutsopoulou2, Antony Symons2, Dorthe Cook3, John M. Lucocq4, Alan R. Prescott4, Anne O'Garra3, Steven C. Ley2 and Philip Cohen1,*

1 MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK
2 Division of Immune Cell Biology, National Institute for Medical Research, Mill Hill, London, NW7 1AA, UK
3 Division of Immunoregulation, National Institute for Medical Research, Mill Hill, London, NW7 1AA, UK
4 Division of Cell Biology and Immunology, College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK

* Authors for correspondence (e-mails: s.rousseau{at}dundee.ac.uk; p.cohen{at}dundee.ac.uk)

Accepted 19 October 2007

Summary

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.

Key words: COT, TNF, MAP kinase, TACE, TLR




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