Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
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A more recent version of this article appeared on July 1, 2008

Published online before print April 24, 2008
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0907652


Received for publication September 24, 2007.
Revised March 20, 2008.
Accepted for publication March 26, 2008.


Article

Thrombin-induced expression of endothelial CX3CL1 potentiates monocyte CCL2 production and transendothelial migration

Milan Popovic , Yves Laumonnier , Ladislav Burysek , Tatiana Syrovets , and Thomas Simmet @

Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany

@ To whom correspondence should be addressed. E-mail: thomas.simmet{at}uni-ulm.de.


   Abstract

CX3CL1 (fractalkine, neurotactin) is the sole CX3C chemokine. It induces monocyte locomotion in its cleaved form, but in its membrane-anchored form, it also acts as an adhesion molecule. The expression of CX3CL1 is up-regulated in endothelial cells by proinflammatory cytokines such as IL-1 or TNF-{alpha}. Here, we studied the effect of the serine protease thrombin on endothelial CX3CL1 induction and its putative relevance for monocyte function. In HUVEC, thrombin triggered a time- and concentration-dependent expression of CX3CL1 at the mRNA and the protein level as shown by RT-PCR, Western immunoblotting, and flow cytometric analysis. Thrombin induced CX3CL1 by activating protease-activated receptor 1 (PAR1) as demonstrated by the use of PAR1-activating peptide and the PAR1-specific antagonist SCH 79797. The thrombin-induced CX3CL1 expression was NF-{kappa}B-dependent, as shown by EMSA, ELISA, and by inhibition of the NF-{kappa}B signaling pathway by the I{kappa}B kinase inhibitor acety-11-keto-{beta}-boswellic acid or by transient overexpression of a transdominant-negative form of I{kappa}B{alpha}. Upon cocultivation of human monocytes with HUVEC, the thrombin-dependent induction of membrane-anchored CX3CL1 in HUVEC triggered monocyte adhesion and an enhanced release of the MCP-1/CCL2 by monocytes and potentiated the monocyte transendothelial migration. Accordingly, the recombinant extracellular domain of CX3CL1 induced CCL2 release by monocytes. Thus, the thrombin-induced monocyte/endothelial cell cross-talk mediated by increased CX3CL1 expression potentiates the CCL2 chemokine generation that might contribute to the recruitment of monocytes into inflamed areas.

Key Words: Mono-Mac-6 • HUVEC • chemokine • protease-activated receptor 1 • coculture







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Copyright © 2008 by the Society for Leukocyte Biology.