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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1761.)
© 2003 American Heart Association, Inc.

Vascular Biology

Mechanisms of Leukotriene B₄–Triggered Monocyte Adhesion

Erik B. Friedrich; Andrew M. Tager; Emerson Liu; Annika Pettersson; Christer Owman; Lance Munn; Andrew D. Luster; Robert E. Gerszten

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.

Correspondence to Robert E. Gerszten, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital East-8307, 149 13th St, Charlestown, MA 02129. 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 ß₁- and ß₂-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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