LEUKOTRIENE D-4 FACILITATES AIRWAY SMOOTH-MUSCLE CELL-PROLIFERATION VIA MODULATION OF THE IGF AXIS
LEUKOTRIENE D-4 FACILITATES AIRWAY SMOOTH-MUSCLE CELL-PROLIFERATION VIA MODULATION OF THE IGF AXIS
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DOI：
10.1152/ajplung.1995.269.2.l151
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发表时间：
1995-08-01
影响因子：
4.9
通讯作者：
GRUNSTEIN, MM
中科院分区：
文献类型：
--
作者：
COHEN, P;NOVERAL, JP;GRUNSTEIN, MM
胰岛素样生长因子（IGF）轴参与调节多种细胞类型（包括气道平滑肌）的增殖。由于气道增生是哮喘和其他肺部疾病的特征，我们检测了强效促炎性类二十烷白三烯D-4（LTD（4））与IGF轴在调节气道平滑肌细胞有丝分裂中的相互作用。在培养的兔气道平滑肌细胞中，IGF-I在次最大浓度下具有促有丝分裂作用，而LTD（4）则无此作用。两种药物联合应用对气道平滑肌细胞有丝分裂有明显的协同作用。通过蛋白质配体印迹法分析气道平滑肌细胞条件培养基，证实LTD（4）诱导的主要IGF结合蛋白IGFBP-2水平显著降低，IGFBP-2被加工到条件培养基中。后一种对IGFBP-2释放的影响与IGFBP-2 mRNA水平的降低无关;然而，LTD（4）处理的气道平滑肌条件培养基显示存在较低分子量形式的IGFBP-2，其通过与IGFs交联和放射性标记的IGFBP-2的特异性蛋白水解作用。IGFBP-2也被发现与气道平滑肌细胞膜相关，在那里它被保护免受LTD（4）诱导的蛋白水解。最后，发现外源性给予IGFBP-2以剂量依赖性方式抑制IGF-I的促有丝分裂作用。总之，这些观察结果提供了新的证据，支持LTD（4）通过诱导IGFBP-2蛋白酶降低IGFBP-2的细胞外水平，从而使更多的游离IGF与其受体相互作用并促进气道平滑肌细胞增殖，从而增强气道平滑肌对IGF-I的促有丝分裂反应。
The insulin-like growth factor (IGF) axis is involved in regulating proliferation in a variety of cell types, including airway smooth muscle. Because airway hyperplasia is a characteristic feature of asthma and other lung diseases, we examined the interaction of the potent proinflammatory eicosanoid leukotriene D-4 (LTD(4)) with the IGF axis in regulating airway smooth muscle cell mitogenesis. In cultured rabbit airway smooth muscle cells, IGF-I but not LTD(4) was mitogenic at submaximal concentrations. The combination of the two agents exerted a significant synergistic effect on airway smooth muscle cell mitogenesis. Analysis of airway smooth muscle cell conditioned medium by Western ligand blotting demonstrated a marked LTD(4)-induced reduction in the levels of the predominant IGF binding protein IGFBP-2, which is elaborated into the conditioned medium. The latter effect on IGFBP-2 release was not associated with a reduction in IGFBP-2 mRNA levels; however, LTD(4)-treated airway smooth muscle conditioned medium demonstrated the presence of a lower molecular weight form of IGFBP-2 by cross-linking to IGFs and specific proteolysis of radiolabeled IGFBP-2. IGFBP-2 was also noted to be associated with airway smooth muscle cell membranes, where it was protected from LTD(4)-induced proteolysis. Finally, exogenous administration of IGFBP-2 was found to inhibit the promitogenic effect of IGF-I in a dose-dependent manner. Collectively, these observations provide new evidence supporting the concept that LTD(4) augments the mitogenic response of airway smooth muscle to IGF-I by inducing an IGFBP-2 protease which decreases the extracellular levels of IGFBP-2, thereby allowing more free IGF to interact with its receptors and promote airway smooth muscle cell proliferation.