Global gene expression analysis of keloid fibroblasts in response to electron beam irradiation reveals the involvement of interleukin-6 pathway
Global gene expression analysis of keloid fibroblasts in response to electron beam irradiation reveals the involvement of interleukin-6 pathway
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DOI：
10.1111/j.0022-202x.2005.23592.x
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发表时间：
2005-04-01
影响因子：
6.5
通讯作者：
Kawanami, O
中科院分区：
文献类型：
--
作者：
Tosa, M;Ghazizadeh, M;Kawanami, O
瘢痕疙瘩是一种病因不明的真皮纤维增生性病变，通常在手术切除后复发。术后辅助电子束（EB）照射已成功用于减少疤痕疙瘩复发。为了对 EB 辐射效应背后的分子机制提供新的见解，我们使用 5000 多个基因的 cDNA 微阵列筛选来评估 EB 辐射和未辐射的疤痕疙瘩和非病变真皮成纤维细胞之间基因表达的早期变化。来自 5 名患者的瘢痕疙瘩和相关非病变真皮的原代成纤维细胞培养物暴露于 15 Gy EB 照射，并在孵育 15 分钟后进行分析。对 EB 照射的早期反应表明，在瘢痕疙瘩成纤维细胞中，96 个（1.8%）基因被调节了 2 倍或更多。上调基因占29.2%（28个基因），下调基因占70.8%（68个基因），表明EB照射后瘢痕疙瘩成纤维细胞中许多基因沉默。许多下调的基因在增强细胞增殖和细胞外基质产生中发挥作用，而一些上调的基因则涉及促进细胞凋亡和细胞外基质（ECM）降解。利用新兴的生物信息学工具并进一步佐证，发现白细胞介素6（IL-6）信号通路主要参与EB照射反应。我们还在瘢痕疙瘩成纤维细胞中发现了 IL-6 及其特异性受体 (IL-6R α) 的共表达，这表明这些细胞中存在 IL-6 自分泌环。这些结果表明，在分子水平上，EB 照射可能通过调节基质系统中诱导剂和抑制剂活性之间稳态平衡的紊乱来阻碍疤痕疙瘩的形成，最有可能通过 IL-6 途径。我们的研究为 EB 照射减少瘢痕疙瘩复发的有益作用背后的分子机制提供了线索，并可能有助于制定治疗和预防这种病变的替代策略。
Keloid is a dermal fibroproliferative lesion of unknown etiology that commonly recurs after surgical excision. Post-operative adjuvant electron beam (EB) irradiation has been successfully used to reduce keloid recurrences. To provide new insights into the molecular mechanism behind the effect of EB irradiation, we used a cDNA microarray screening of more than 5000 genes to assess early changes in gene expression between EB-irradiated and non-irradiated keloid and non-lesional dermal fibroblasts. Primary fibroblast cultures from keloid and associated non-lesional dermis obtained from five patients were exposed to 15 Gy EB irradiation and analyzed after 15 min incubation. Early response to EB irradiation showed that 96 (1.8%) genes were modulated 2-fold or more in keloid fibroblasts. Upregulated genes accounted for 29.2% (28 genes), whereas downregulated genes comprised 70.8% (68 genes), indicating a silencing of many genes in keloid fibroblasts after EB irradiation. Many of the downregulated genes play roles in the enhancement of cell proliferation and extracellular matrix production, whereas several of the upregulated genes involves in the promotion of apoptosis and extracellular matrix (ECM) degradation. Using emerging bioinformatic tools and further corroboration, the interleukin 6 (IL-6) signaling pathway was found to be mainly involved in EB irradiation response. We also showed co-expression of IL-6 and its specific receptor (IL-6R alpha) in keloid fibroblasts that points to the existence of an IL-6 autocrine loop in these cells. These results suggested that at the molecular level, EB irradiation might hinder keloid formation by regularizing disturbances in the homeostatic equilibrium between inducer and inhibitor activities in the matrix system most likely through the IL-6 pathway. Our study provides clues for the molecular mechanism(s) behind the beneficial effect of EB irradiation in reducing keloid recurrences and may help develop alternative strategies for the therapy and prophylaxis of this lesion.