Hypoxia-induced HIF-1 alpha accumulation is augmented in a co-culture of keloid fibroblasts and human mast cells: involvement of ERK1/2 and PI-3K/Akt.
Hypoxia-induced HIF-1 alpha accumulation is augmented in a co-culture of keloid fibroblasts and human mast cells: involvement of ERK1/2 and PI-3K/Akt.
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DOI：
10.1016/j.yexcr.2005.10.006
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发表时间：
2006-01
影响因子：
3.7
通讯作者：
Qunzhou Zhang;C. Oh;D. Messadi;H. Duong;A. Kelly;C. Soo;Lina Wang;A. Le
中科院分区：
文献类型：
--
作者：
Qunzhou Zhang;C. Oh;D. Messadi;H. Duong;A. Kelly;C. Soo;Lina Wang;A. Le
疤痕疙瘩代表一种长期的炎症纤维化状态，其区域表现出独特的组织学特征，其特征是丰富的细胞外基质基质、炎症细胞（包括肥大细胞）的局部浸润以及丰富的细胞因子环境。我们实验室之前的研究表明，与邻近的普通皮肤相比，瘢痕疙瘩组织中 HIF-1α 和 VEGF 蛋白的表达水平更高。为了进一步研究疤痕疙瘩中HIF-1α和VEGF表达升高的机制，我们将疤痕疙瘩成纤维细胞和肥大细胞（HMC-1）的共培养物暴露于缺氧条件下，并研究了HIF-1α及其靶基因VEGF的表达。我们的结果表明，在允许细胞与细胞直接接触的条件下与 HMC-1 细胞共培养时，瘢痕疙瘩成纤维细胞中缺氧依赖性 HIF-1α 蛋白积累和 VEGF 表达增加。但在 Transwell 共培养系统中没有观察到这种增强，而成纤维细胞和 HMC-1 细胞被多孔膜分开。我们的结果还表明，缺氧介导的 ERK1/2 和 Akt 激活的增强需要肥大细胞和瘢痕疙瘩成纤维细胞之间直接的细胞间相互作用，并且 ERK1/2 和 Akt 的激活参与共培养系统中缺氧依赖性 HIF-1α 蛋白的积累和 VEGF 的表达。这些发现表明，在缺氧条件下，肥大细胞可能通过与成纤维细胞的直接细胞间相互作用，至少部分地促进疤痕疙瘩中 HIF-1α 和 VEGF 蛋白表达的升高。
Keloids represent a prolonged inflammatory fibrotic state with areas that display distinctive histological features characterized by an abundant extracellular matrix stroma, a local infiltration of inflammatory cells including mast cells, and a milieu of enriched cytokines. Previous studies from our laboratory demonstrated an intrinsic higher level of HIF-1α and VEGF protein expression in keloid tissues compared with their adjacent unremarkable skins. To further investigate the mechanisms underlying the elevated expression of HIF-1α and VEGF in keloids, we exposed a co-culture of keloid fibroblasts and mast cells (HMC-1) to hypoxic conditions and studied the expression of HIF-1α and its target gene, VEGF. Our results showed that hypoxia-dependent HIF-1α protein accumulation and VEGF expression is augmented in keloid fibroblasts when co-cultured with HMC-1 cells under the condition where direct cell–cell contact is allowed. But such augmentation is not observed in the transwell co-culture system whereas fibroblasts and HMC-1 cells were separated by a porous membrane. Our results also indicated that the enhancement of hypoxia-mediated activation of ERK1/2 and Akt requires direct cell–cell interaction between mast cells and keloid fibroblasts, and activation of both ERK1/2 and Akt is involved in the hypoxia-dependent HIF-1α protein accumulation and VEGF expression in the co-culture system. These findings suggest that under hypoxic conditions mast cells may contribute, at least in part, to an elevated expression of HIF-1α and VEGF protein in keloids via direct cell–cell interaction with fibroblasts.