β2-Integrin adhesion caused by eotaxin but not IL-5 is blocked by PDE-4 inhibition and β2-adrenoceptor activation in human eosinophils

被引:13
作者
Liu, J
Muñoz, NM
Meliton, AY
Zhu, XD
Lambertino, AT
Xu, C
Myo, S
Myou, S
Boetticher, E
Johnson, M
Leff, AR
机构
[1] Univ Chicago, Dept Med MC6076, Pulm & Crit Care Med Sect, Chicago, IL 60637 USA
[2] GlaxoSmithKline Inc, Uxbridge, Middx, England
[3] Univ Chicago, Dept Neurobiol, Chicago, IL 60637 USA
[4] Univ Chicago, Dept Physiol & Pharmacol, Chicago, IL 60637 USA
[5] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA
[6] Univ Chicago, Dept Anesthesia & Crit Care, Chicago, IL 60637 USA
[7] Univ Chicago, Div Biol Sci, Comm Clin Pharmacol, Chicago, IL 60637 USA
[8] Univ Chicago, Div Biol Sci, Comm Pharmacogenom, Chicago, IL 60637 USA
[9] Univ Chicago, Div Biol Sci, Comm Cell Physiol & Mol Med, Chicago, IL 60637 USA
关键词
PDE-4; rolipram; eosinophils; salmeterol; cPLA(2); ERK; CD11b; beta; 2-integrin;
D O I
10.1016/j.pupt.2003.10.005
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
We investigated the effect and mechanism(s) of PDE-4 treatment with concurrent beta(2)-adrenoceptor stimulation on human eosinophil adhesion mediated by beta(2)-integrin in vitro. Eosinophils were pretreated with either rolipram, a PDE-4 inhibitor, alone or combined with salmeterol, a beta(2)-adrenoceptor agonist, before activation with either eotaxin or IL-5. beta(2)-integrin mediated adhesion was assessed as adherence to BSA, an established surrogate for ICAM-1. Rolipram caused progressive blockade (77.7 +/- 6.2%) of adhesion elicited by eotaxin. Maximal blockade of IL-5-activated adhesion by rolipram was substantially less (29.9 +/- 5.2%). Salmeterol + rolipram synergistically enhanced the blockade of eotaxin-activated adhesion. Eotaxin also caused similar to 50% increase in surface CD11b expression, which was blocked additively by rolipram + salmeterol. By contrast, CD11b upregulation caused by IL-5 was not blocked by rolipram + salmeterol. Rolipram also attenuated cPLA, phosphorylation caused by eotaxin but did not block IL-5-induced phosphorylation. We conclude that rolipram blocks expression of CD11b and inhibits cPLA(2) phosphorylation in human eosinophils, thus blocking eotaxin-induced adhesion of beta(2)-integrin. IL5-induced adhesion likely utilizes a different upstream mechanism in regulation of integrin adhesion. (C) 2004 Elsevier Ltd. All rights reserved.
引用
收藏
页码:73 / 79
页数:7
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