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International Immunology Advance Access published online on August 13, 2007
International Immunology, doi:10.1093/intimm/dxm050
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© The Japanese Society for Immunology. 2007. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Expression and function of mixed lineage kinases in dendritic cells

Matthew E. Handley, Jane Rasaiyaah, James Barnett, Manish Thakker, Gabriele Pollara, David R. Katz and Benjamin M. Chain

Department of Immunology and Molecular Pathology, University College London, Windeyer Institute, 46 Cleveland Street, London W1T 4JF, UK

Correspondence to: Correspondence to: B. M. Chain; E-mail: b.chain{at}ucl.ac.uk

Dendritic cells (DCs) sense the presence of conserved microbial structures in their local microenvironment via specific pattern recognition receptors (PRRs). This leads to a programme of changes, which include migration and activation, and enables them to induce adaptive T cell immunity. Mitogen-activated protein kinases (MAPKs) are implicated in this response, but the pathways leading from PRR ligation to MAPK activation, and hence DC activation, are not fully understood. Recent studies in the nervous system have suggested that the mixed lineage kinase (MLK) family of MAPK kinase kinase proteins may be involved as an intermediary step between PRRs and MAPKs. Therefore, in this study, we have used a well-established DC model to explore the role of MLKs in these cells. Messenger RNA for MLKs 2, 3, 4 and DLK and protein for MLKs 2, 3 and DLK are found in DC. DC activation in response to model PRR ligands, such as LPS or poly (I:C), is accompanied by phosphorylation of MLK3. In contrast, another known PRR ligand, zymosan, induces little MLK3 phosphorylation. Inhibition of MLK activity using a pharmacological inhibitor, CEP11004, blocks p38 and Jun N-terminal kinase (JNK) MAPK activation in response to LPS and poly (I:C), but not zymosan. The inhibition is associated with a block in DC activation as measured by cell-surface marker expression and cytokine secretion. Thus, MLKs are expressed in DC, and are implicated in DC activation, and the involvement of MLKs appears to be selective, depending on the nature of the DC stimulus.

Keywords: dendritic cells, mixed lineage kinases, toll-like receptors

Transmitting editor: M. Feldmann

Received 25 August 2006, accepted 30 March 2007.


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