Lipoxins induce actin reorganization in monocytes and macrophages but not in neutrophils - Differential involvement of Rho GTPases
Lipoxins induce actin reorganization in monocytes and macrophages but not in neutrophils - Differential involvement of Rho GTPases
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DOI：
10.1016/s0002-9440(10)61175-3
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发表时间：
2002-06-01
影响因子：
6
通讯作者：
Godson, C
中科院分区：
文献类型：
--
作者：
Maderna, P;Cottell, DC;Godson, C
脂氧素（LXs）是内源性产生的类二十烷酸，其抑制中性粒细胞运输并刺激单核细胞衍生的巨噬细胞对凋亡中性粒细胞的非炎性吞噬。在这项研究中，我们评估了LX对人类白细胞中细胞超微结构和肌动蛋白重组的影响，并研究了在这种情况下促进LX生物活性的信号事件。LXA（4）（10（-9）mol/L）、稳定的合成类似物15-（R/S）-甲基-LXA（4）和16-苯氧基-LXA（4）（10（-11）mol/L）可引起单核细胞和巨噬细胞超微结构和肌动蛋白重排的明显改变，而LX前体15-（S）-HETE则无此作用。相反，在基础条件下和用白三烯B-4刺激后，LXA（4）不改变中性粒细胞中肌动蛋白分布。抑制剂Y-27632阻断Rho激酶可阻止LYA（4）引发的巨噬细胞肌动蛋白重组。为了研究特定的小GTP酶在LX诱导的肌动蛋白重排中的作用，我们使用了分化为巨噬细胞样表型的THP-1细胞。用LX刺激THP-1细胞，而不是用15-（S）-HETE刺激，通过免疫印迹显示膜相关RhoA和Rac增加。此外，在对LXA的反应中观察到Rho活性增加两倍（4）。LX诱导的肌动蛋白重排和RhoA活化可被细胞渗透性cAMP类似物8-Br-cAMP抑制，而蛋白激酶A抑制剂Rp-cAMP模拟LXA的作用（4）。这些数据表明，LX刺激RhoA和Rac依赖性细胞骨架重组，有助于LX在炎症消退中的潜在作用。
Lipoxins (LXs) are endogenously produced eicosanoids that inhibit neutrophil trafficking and stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. in this study we assessed the effect of LXs on cell ultrastructure and actin reorganization in human leukocytes and investigated the signaling events that subserve LX bioactivity in this context. LXA(4) (10(-9) mol/L), the stable synthetic analogues 15-(R/S)-methyl-LXA(4) and 16-phenoxy-LXA(4) (10(-11) mol/L), but not the LX precursor 15-(S)-HETE, induced marked changes in ultrastructure and rearrangement of actin in monocytes and macrophages. in contrast, LXA(4) did not modify actin distribution in neutrophils under basal conditions and after stimulation with leukotriene B-4. Blockade of Rho kinases by the inhibitor Y-27632 prevented LYA(4)-triggered actin reorganization in macrophages. To investigate the role of the specific small GTPases in LX-induced actin rearrangement we used THP-1 cells differentiated to a macrophage-like phenotype. THP-1 cells stimulated with LXs, but not with 15-(S)-HETE, showed an increase in membrane-associated RhoA and Rac by immunoblotting. Additionally, a twofold increase in Rho activity was seen in response to LXA(4). LX-induced actin rearrangement and RhoA activation were inhibited by the cell permeable cAMP analogue 8-Br-cAMP, whereas Rp-cAMP, an inhibitor of protein kinase A, mimicked the effect of LXA(4). These data demonstrate that LXs stimulate RhoA- and Rac-dependent cytoskeleton reorganization, contributing to the potential role of LXs in the resolution of inflammation.