on August 28, 2003
Published online before print August 28, 2003, doi: 10.1161/01.ATV.0000092941.77774.3C
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Submitted on June 18, 2003
Accepted on July 31, 2003
Mechanisms of Leukotriene B4-Triggered Monocyte Adhesion
Erik B. Friedrich ;
From the Center for Immunology and Inflammatory Diseases (E.B.F., A.M.T., E.L., A.D.L., R.E.G.), the Cardiology Division (R.E.G.), and the Department of Radiation Oncology (L.M.), Massachusetts General Hospital, Charlestown, Mass; and the Wallenberg Neuroscience Center (A.P., C.O.), Lund University, Lund, Sweden.
* To whom correspondence should be addressed. E-mail: rgerszten{at}partners.org.
Objective--Leukotriene B4 (LTB4) has been implicated in the trafficking of monocytes to inflammatory pathologic conditions, such as transplant rejection and atherosclerosis. The aim of this study was to determine the mechanisms by which LTB4 contributes to monocyte capture from the circulation.
Methods and Results--In in vitro and in vivo vascular models, the lipid chemoattractant LTB4 was an equipotent agonist of monocyte adhesion compared with the chemokine monocyte chemoattractant protein-1 (MCP-1). Adenoviral gene transfer of specific endothelial adhesion molecules and blocking monoclonal antibody studies demonstrated that LTB4 triggers both 
1- and 2-integrin-dependent adhesion. Flow cytometry studies suggested that changes in integrin avidity or affinity, rather than alterations of integrin surface expression, were responsible for the chemoattractant-triggered arrest. Surprisingly, in contrast to the peptide chemokine MCP-1, LTB4 did not activate the phosphoinositide 3-kinase pathway, which is a functionally critical step in chemokine-triggered effector functions.
Conclusions--LTB4 is a potent trigger of monocyte adhesion under flow yet mediates its effects via pathways that appear to differ from peptide chemoattractants. A better understanding of the mechanisms of LTB4-induced monocyte trafficking might shed insight into disease pathogenesis and pinpoint critical steps for therapeutic intervention for multiple human inflammatory pathologic conditions.
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