Published online before print January 27, 2005, doi: 10.1161/01.ATV.0000157154.14474.3b
© 2005 American Heart Association, Inc.
Vascular Biology |
Involvement of JAM-A in Mononuclear Cell Recruitment on Inflamed or Atherosclerotic Endothelium
Inhibition by Soluble JAM-A
From the Departments of Cardiovascular Molecular Biology (G.O., L.F., T.B., A.S., M.L., A.Z., E.A.L., C.W.), Cardiology (A.S., A.Z., C.W.), and Anesthesiology (T.B.), University Hospital, Aachen, Germany.
Correspondence to Dr Christian Weber, Kardiovaskuläre Molekularbiologie, Universitätsklinikum Aachen, Rheinisch-Westfälische Technische Hochschule, Pauwelsstr. 30, 52074 Aachen, Germany. E-mail cweber{at}ukaachen.de
Objective— The junctional adhesion molecule (JAM)-A on endothelium contributes to the inflammatory recruitment of mononuclear cells involving engagement of its integrin receptor lymphocyte function-associated antigen (LFA)-1. It is unknown whether these functions can be inhibited by soluble forms of JAM-A, whether JAM-A is expressed on atherosclerotic endothelium, and whether it participates in atherogenic recruitment of mononuclear cells.
Methods and Results— Adhesion assays revealed that LFA-1–mediated binding of mononuclear cells to intercellular adhesion molecule (ICAM)-1 or cytokine-costimulated endothelium was dose-dependently inhibited by soluble JAM-A.Fc (sJAM-A.Fc). Similarly, sJAM-A.Fc reduced stromal cell-derived factor (SDF)-1
–triggered transendothelial chemotaxis of activated T cells and their SDF-1–triggered arrest on cytokine-costimulated endothelium under flow conditions. Immunofluorescence analysis revealed an upregulation of JAM-A on early atherosclerotic endothelium of carotid arteries from apolipoprotein E-deficient (apoE–/–) mice fed an atherogenic diet. In ex vivo perfusion assays, pretreatment of mononuclear cells with sJAM-A.Fc inhibited their very late antigen (VLA)-4–independent accumulation on atherosclerotic endothelium of these arteries.
Conclusions— Soluble forms of JAM-A can be effectively applied to inhibit distinct steps of mononuclear cell recruitment on inflamed or atherosclerotic endothelium. In conjunction with its expression on atherosclerotic endothelium, this suggests a functional contribution of JAM-A to atherogenesis.
We studied the effect of soluble JAM-A (sJAM-A.Fc) on atherogenic recruitment of mononuclear cells. Because sJAM-A.Fc can inhibit distinct steps of mononuclear cell recruitment, ie, adhesion and transendothelial chemotaxis, on inflamed and atherosclerotic endothelium, our data suggest a functional contribution of JAM-A to atherogenesis.
Key Words: cell adhesion molecules • endothelium • inflammation • atherosclerosis
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