Peroxisome proliferator-activated receptor and retinoid X receptor ligands inhibit monocyte chemotactic protein-1-directed migration of monocytes
Peroxisome proliferator-activated receptor and retinoid X receptor ligands inhibit monocyte chemotactic protein-1-directed migration of monocytes
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DOI：
10.1016/s0014-2999(00)00461-1
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发表时间：
2000-08-11
影响因子：
5
通讯作者：
Law, RE
中科院分区：
文献类型：
--
作者：
Kintscher, U;Goetze, S;Law, RE
单核细胞趋化蛋白-1(MCP-1)介导的单核细胞跨内皮细胞迁移在炎症性疾病的发生发展中起关键作用。单核细胞对组织的侵袭需要降解细胞外基质，这一过程涉及到基质金属蛋白酶。我们研究了过氧化物酶体增殖物激活受体(PPAR)γ、α和维甲酸X受体α(RXRα)配体对人急性单核细胞白血病细胞系(THP-1)单核细胞趋化蛋白-1(MCP-1)迁移和基质金属蛋白酶表达的影响。PPARγ配体可减弱MCP-1诱导的细胞迁移，曲格列酮和罗格列酮的IC50分别为2.8mU和4.8mU。PPARα配体WY-14643(IC_(50)：0.9mM)和5，8，11，14-二十碳四酸(IC_(50)：9.9mM)和有效的RXRα配体AGN 4204(IC_(50)：3.6 nM)也能抑制单核细胞迁移。曲格列酮、罗格列酮或AGN 4204可抑制佛波酯诱导的基质金属蛋白酶-9的表达。而PPARα激动剂WY-14643和5，8，11，14-二十碳四烯酸则无抑制作用。AgN 4204可增加PMA诱导的基质金属蛋白酶组织抑制因子-1(TIMP-1)的表达，而所有PPAR配体均无此作用。在没有基质屏障的情况下，所有的PPAR和RXRα配体都可阻断THP-1单核细胞的趋化作用。本研究表明，激活PPAR和RXRα可阻断MCP-1诱导的单核细胞迁移，至少部分是通过它们对基质金属蛋白酶-9或TIMP-1的产生或趋化作用来实现的。(C)2000 Elsevier Science B，V.保留所有权利。
Monocyte chemotactic protein-1 (MCP-1)-directed transendothelial migration of monocytes plays a key role in the development of inflammatory diseases. Infiltration of tissues by monocytes requires degradation of extracellular matrices, a process that involves matrix metalloproteinases, We studied the effects of peroxisome proliferator-activated receptor (PPAR) gamma, alpha, and retinoid X receptor alpha (RXR alpha) ligands on MCP-1-directed migration and matrix metalloproteinase expression of a human acute monocytic leukemia cell line (THP-1). PPAR gamma ligands attenuated MCP-1induced migration, with 50% inhibition (IC50) at 2.8 mu M for troglitazone and 4.8 mu M for rosiglitazone. PPAR alpha ligands WY-14643 (IC50: 0.9 mu M) and 5,8,11,14-eicosatetranoic acid (IC50: 9.9 mu M), and the potent RXR alpha ligand AGN 4204 (IC50: 3.6 nM) also blocked monocyte migration. Troglitazone, rosiglitazone, or AGN 4204 inhibited phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase-9 expression. PPAR alpha activators WY-14643 and 5,8,11,14-eicosatetraynoic acid, however, had no inhibitory effect. AGN 4204 increased PMA-induced tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) expression, whereas all PPAR ligands showed no effect. All PPAR and RXR alpha ligands blocked chemotaxis of THP-1 monocytes in the absence of a matrix barrier, This study demonstrates that activated PPARs and RXR alpha, block MCP-1-directed monocyte migration, mediated, at least in part, through their effects on matrix metalloproteinase-9 or TIMP-1 production, or chemotaxis. (C) 2000 Elsevier Science B,V. All rights reserved.