Mechanisms of leukotriene B4--triggered monocyte adhesion.
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.


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 beta1- and beta2-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.
Friedrich
Erik B
EB
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown 02129, USA.
Tager
Andrew M
AM
Liu
Emerson
E
Pettersson
Annika
A
Owman
Christer
C
Munn
Lance
L
Luster
Andrew D
AD
Gerszten
Robert E
RE
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000502:physiology; D002630:Chemotactic Factors / Q000494:pharmacology; D004730:Endothelium, Vascular; D005434:Flow Cytometry; D006801:Humans; D007975:Leukotriene B4 / Q000502:physiology*; D008638:Mesenteric Arteries; D009000:Monocytes / Q000737:chemistry / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018102:Receptors, Leukotriene B4 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction
D018932:Chemokine CCL2; D002630:Chemotactic Factors; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4