Leukotriene D4 and eosinophil transendothelial migration, superoxide generation, and degranulation via beta2 integrin.
BACKGROUND
Evidence indicates that cysteinyl leukotriene (cysLT) 1 receptor antagonists possess anti-inflammatory properties in asthmatic patients in vivo. Although the exact mechanisms of these actions remain unknown, cysLTs regulate the locomotion and functions of eosinophils. We previously reported that leukotriene D4 augments the expression of eosinophil beta2 integrin and the adhesion of eosinophils to rh intercellular adhesion molecule 1 via beta2 integrin.


OBJECTIVE
To examine whether leukotriene D4 modifies the transendothelial migration (TEM) and effector functions of eosinophils.


METHODS
We evaluated the effects of leukotriene D4 on (1) eosinophil TEM across human umbilical vein endothelial cells, (2) superoxide anion (O2-) generation, and (3) eosinophil-derived neurotoxin release in eosinophils isolated from the blood of healthy individuals.


RESULTS
Leukotriene D4 (0.1-1 microM) significantly induced eosinophil TEM, O2- generation, and eosinophil-derived neurotoxin release. Pranlukast, a cysLT1 receptor antagonist, significantly inhibited all of these parameters, although the inhibitory effect on O2- generation was partial. All of these responses were significantly inhibited by anti-beta2 integrin but not by anti-alpha4 integrin antibodies.


CONCLUSIONS
Leukotriene D4 directly up-regulates the TEM and effector functions of eosinophils mainly via the cysLT1 receptor and beta2 integrin. These effects of leukotriene D4 probably contribute to the manifestation of eosinophil inflammation in asthmatic airways.
Saito
Keiko
K
Department of Respiratory Medicine, Saitama Medical School, Saitama, Japan.
Nagata
Makoto
M
Kikuchi
Izumi
I
Sakamoto
Yoshio
Y
D000328:Adult; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects* / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism; D047208:Eosinophil-Derived Neurotoxin / Q000187:drug effects / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects* / Q000276:immunology; D005260:Female; D006801:Humans; D039641:Integrin beta Chains / Q000187:drug effects / Q000276:immunology; D017998:Leukotriene D4 / Q000494:pharmacology*; D008297:Male; D013481:Superoxides / Q000276:immunology*
D039641:Integrin beta Chains; D013481:Superoxides; D017998:Leukotriene D4; D047208:Eosinophil-Derived Neurotoxin