Activation and transforming growth factor-β production in eosinophils by hyaluronan
Activation and transforming growth factor-β production in eosinophils by hyaluronan
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DOI：
10.1165/ajrcmb.23.4.3875
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发表时间：
2000-10-01
影响因子：
6.4
通讯作者：
Shirato, K
中科院分区：
文献类型：
--
作者：
Ohkawara, Y;Tamura, G;Shirato, K
为了研究细胞外基质糖胺聚糖透明质酸（HA）是否调节嗜酸性粒细胞活化和嗜酸性粒细胞产生转化生长因子（TGF）-β，人外周血嗜酸性粒细胞从12名轻度至中度哮喘患者或6名健康受试者中分离纯化HA（纯度> 99%），并与浓度递增的低分子量（mol wt）HA一起孵育（约0.2 × 10（6）D）或高分子量HA（3.0至约5.8 × 10（6）D）。我们发现，低分子量HA在第2天和第4天对哮喘患者和健康受试者中的嗜酸性粒细胞存活率具有显著影响，且呈剂量依赖性。而高分子量HA对嗜酸性粒细胞存活的影响小于低分子量HA。HA介导的嗜酸性粒细胞存活被HA特异性受体CD 44的阻断性单克隆抗体部分但显著抑制（约50%抑制），并且在很大程度上被抗粒细胞巨噬细胞集落刺激因子（CM-CSF）中和抗体抑制，但不被抗白细胞介素（IL）-3或抗IL-5中和抗体抑制。此外，低mol wt HA以剂量依赖性方式增加了嗜酸性粒细胞的CM-CSF信使RNA（mRNA）表达和蛋白分泌，表明HA介导的嗜酸性粒细胞存活主要是由于通过部分CD 44信号传导诱导CM-CSF释放。此外，我们证明，低分子量HA导致嗜酸性粒细胞的形态学变化，如从圆形转化为纺锤形和同型聚集，上调细胞间粘附分子-1的表达，并增加TGF-β mRNA的表达和嗜酸性粒细胞的蛋白分泌。这些观察结果表明，嗜酸性粒细胞和低mot wt细胞外基质之间的相互作用，因此，嗜酸性粒细胞可能有助于气道炎症和气道重建的调节的新途径。
To investigate whether extracellular matrix glycosaminoglycan hyaluronan (HA) modulates eosinophil activation and transforming growth factor (TGF)-beta production by eosinophils, human peripheral blood eosinophils (purity > 99%) from 12 patients with mild to moderate asthma or six healthy subjects were isolated and incubated with increasing concentrations of low molecular weight (mol wt) HA (approximate to 0.2 x 10(6) D) or high mol wt HA (3.0 to approximate to 5.8 x 10(6) D). We found that the low mol wt HA has a pronounced effect on eosinophil survival in both patients with asthma and healthy subjects in a dose-dependent fashion on Days 2 and 4. Whereas the high mol wt HA had a smaller effect on eosinophil survival than did the low mol wt HA. The HA-mediated eosinophil survival was partially but significantly inhibited ( approximate to 50% inhibition) by a blocking monoclonal antibody for CD44, a specific receptor of HA, and largely inhibited by an anti-granulocyte macrophage colony-stimulating factor (CM-CSF) neutralizing antibody but not by an anti-interleukin (IL)-3 or anti-IL-5 neutralizing antibody. In addition, the low mol wt HA increased CM-CSF messenger RNA (mRNA) expression and protein secretion by eosinophils in a dose-dependent fashion, suggesting that the HA-mediated eosinophil survival is due mainly to induction of CM-CSF release through partial CD44 signaling. Furthermore, we demonstrated that the low mol wt HA results in morphologic changes in eosinophils such as transforming from a round to a spindle shape and in homotypic aggregation, upregulates intercellular adhesion molecule-1 expression, and increases TGF-beta mRNA expression and protein secretion by eosinophils. These observations suggest previously unforeseen interactions between eosinophils and low mot wt extracellular matrix and, thus, novel pathways by which eosinophils may contribute to the regulation of airway inflammation and airway re-modeling.