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International Immunology Advance Access published online on October 24, 2008
International Immunology, doi:10.1093/intimm/dxn116
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© The Author 2008. Published by Oxford University Press on behalf of The Japanese Society for Immunology. All rights reserved.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press and The Japanese Society for Immunology are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Tribbles-2 is a novel regulator of inflammatory activation of monocytes

Katalin Eder1,*, Hongtao Guan1,*, Hye Y. Sung1,*, Jon Ward1, Adrienn Angyal2, Michelle Janas3, Gabriella Sarmay2, Erno Duda4, Martin Turner3, Steven K. Dower1, Sheila E. Francis1, David C. Crossman1 and Endre Kiss-Toth1

1 Cardiovascular Research Unit, University of Sheffield, Sheffield, UK
2 Department of Immunology, Lorand Eotvos University, Budapest, Hungary
3 Babraham Institute, Cambridge, UK
4 Institute of Biochemistry, Biological Research Centre, Szeged, Hungary

Correspondence to: Correspondence to: E. Kiss-Toth, Cardiovascular Research Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK; E-mail: e.kiss-toth{at}sheffield.ac.uk

Inflammatory activation of monocytes is an essential part of both innate immune responses and the pathogenesis of conditions such as atherosclerosis. However, the mechanisms which modulate the response of monocytes to inflammatory stimuli are still poorly understood. Here, we report that tribbles-2 (trb-2) is a novel regulator of inflammatory activation of monocytes. Down-regulation of trb-2 levels potentiates LPS-induced IL-8 production via enhanced activation of the extracellular signal-regulated kinase and jun kinase mitogen-activated protein kinase (MAPK) pathways. In keeping with this, the endogenous level of trb-2 expression in human primary monocytes is inversely correlated to the cell’s ability to produce IL-8. We show that trb-2 is a binding partner and a negative regulator of selected MAPKs. The potential in vivo relevance of these findings is highlighted by the observation that modified low-density lipoprotein profoundly down-regulates trb-2 expression, which may, in turn, significantly contribute to the inflammatory processes in the development of vascular disease. Taken together, our results define trb-2 as a potent novel regulator of monocyte biology, controlling the activation of these cells.

Keywords: inflammation, IL-8, MAP kinases, tribbles

* These authors contributed equally to this study.

Transmitting editor: A. Falus

Received 16 July 2008, accepted 24 September 2008.


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