Role of p38 mitogen-activated protein kinase in chemokine-induced emigration and chemotaxis in vivo
Role of p38 mitogen-activated protein kinase in chemokine-induced emigration and chemotaxis in vivo
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DOI：
10.4049/jimmunol.167.11.6552
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发表时间：
2001-12-01
影响因子：
4.4
通讯作者：
Kubes, P
中科院分区：
文献类型：
--
作者：
Cara, DC;Kaur, J;Kubes, P
已经提出，L-选择素与配体的接合激活p38丝裂原活化蛋白激酶（MAPK），并且可以影响白细胞滚动的下游事件，包括粘附和移出。使用一种新的趋化性测定在体内，我们可视化缓慢释放的趋化因子从琼脂糖凝胶定位350妈妈从毛细血管后小静脉，诱导定向迁移（趋化性）的中性粒细胞。在该系统中，角质形成细胞衍生的细胞因子诱导p38 MAPK磷酸化，其磷酸化下游蛋白（ATF-2）。后一事件被本研究中使用的p38抑制剂的浓度阻断。用两种不同的p38抑制剂：SKF 86002和SB 203580处理小鼠。无论是抑制剂影响滚动或粘附在微血管。在炎症刺激前30分钟静脉注射SFK 86002（5、10和20 mg/kg），在20 mg/kg剂量下抑制了迁移细胞的总数（62%，p < 0.05），尽管血管内存在许多贴壁细胞。用20 mg/kg的第二p38抑制剂SB 203580观察到类似的抑制（67%，p < 0.05）。除了迁移外，两种p38抑制剂都损害了迁移细胞通过组织向趋化刺激迁移的能力。事实上，大多数p38转运蛋白治疗的动物中的迁移的白细胞保持在50 μ m的小静脉。用SKF 86002（0.7 mM）对组织进行灌注以仅影响迁移的而非血管白细胞，未导致迁移受损，但远离血管壁的趋化性显著降低。同样，大多数迁移的白细胞保持在血管的50 μ m内。我们的研究结果表明，p38不影响滚动或粘附，但它是参与白细胞迁移和趋化性，通过角质形成细胞衍生的细胞因子在体内的反应。
It has been proposed that L-selectin engagement with ligand activates p38 mitogen-activated protein kinase (MAPK) and can impact on downstream events of leukocyte rolling, including adhesion, and emigration. Using a novel chemotactic assay in vivo, we visualized slow release of chemokine from an agarose gel positioned 350 mum from a postcapillary venule, which induced directed migration (chemotaxis) of neutrophils. In this system, keratinocyte-derived cytokine induced phosphorylation of p38 MAPK, which phosphorylated a downstream protein (ATF-2). This latter event was blocked by the concentration of p38 inhibitors used in this study. Mice were treated with two different p38 inhibitors: SKF86002 and SB203580. Neither inhibitor affected rolling or adhesion in microvessels. Intravenous treatment with SFK86002 (5, 10, and 20 mg/kg) 30 min before the inflammatory stimulus inhibited the total number of emigrated cells at a dose of 20 mg/kg (62%, p < 0.05), despite the presence of many adherent cells within the vessels. A similar inhibition was observed with 20 mg/kg of a second p38 inhibitor SB203580 (67%, p < 0.05). In addition to emigration, both p38 inhibitors impaired the ability of emigrated cells to migrate through the tissue toward the chemotactic stimulus'. In fact, the majority of emigrated leukocytes in p38 inhibitor-treated animals remained within 50 mum of the venule. Superfusion of the tissue with SKF86002 (0.7 mM) to impact only on emigrated and not vascular leukocytes resulted in no impairment in emigration, but in a significant reduction in chemotaxis away from the vessel wall. Again, the majority of emigrated leukocytes remained within 50 mum of the blood vessel. Our results suggest that p38 does not affect rolling or adhesion, but that it is involved in leukocyte emigration and chemotaxis through interstitium in response to keratinocyte-derived cytokine in vivo.