Cytokine Profiling and Stat3 Phosphorylation in Epithelial-Mesenchymal Interactions between Keloid Keratinocytes and Fibroblasts
Cytokine Profiling and Stat3 Phosphorylation in Epithelial-Mesenchymal Interactions between Keloid Keratinocytes and Fibroblasts
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DOI：
10.1038/jid.2008.337
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发表时间：
2009-04-01
影响因子：
6.5
通讯作者：
Cao, Xinmin
中科院分区：
文献类型：
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作者：
Lim, Cheh P.;Phan, Toan T.;Cao, Xinmin
我们先前报道了瘢痕疙瘩成纤维细胞中信号转导子和转录激活子3（Stat 3）激活的增加，这有助于胶原蛋白的产生、细胞增殖和迁移。我们进一步研究了在非共培养和共培养条件下，上皮-间充质相互作用对正常和瘢痕疙瘩成纤维细胞中Stat 3的影响。与非共培养的正常成纤维细胞相比，瘢痕疙瘩成纤维细胞中的pY 705 Stat 3更高。然而，与正常成纤维细胞相比，当与它们各自的角质形成细胞共培养超过5天时，在瘢痕疙瘩成纤维细胞中观察到pY 705 Stat 3的更剧烈的降低。为了探索这种旁分泌效应，我们通过细胞因子阵列检测了细胞因子的分泌。在非共培养或共培养条件下，在瘢痕疙瘩成纤维细胞和角质形成细胞中检测到细胞因子产生的改变。IL-6、IL-8、单核细胞趋化蛋白-1、金属蛋白酶组织抑制因子-1和金属蛋白酶组织抑制因子-2是主要的细胞因子。血管生成素，制瘤素M（OSM），血管内皮细胞生长因子，IGF结合蛋白-1，osteoprotegerin和转化生长因子β 2存在于瘢痕疙瘩角质形成细胞成纤维细胞共培养，但在正常角质形成细胞成纤维细胞共培养缺席。在正常和瘢痕疙瘩成纤维细胞中，仅IL-6和OSM刺激强的pY 705 Stat 3和细胞增殖。其他细胞因子增加了瘢痕疙瘩成纤维细胞的增殖，但不是正常的成纤维细胞，这表明瘢痕疙瘩成纤维细胞的状态改变。多种细胞因子可能有助于瘢痕疙瘩的发病机制和组合中和抗体/细胞因子治疗可能是有效的改善瘢痕疙瘩疤痕。
We previously reported an increase in signal transducer and activator of transcription 3 (Stat3) activation in keloid fibroblasts, which contributes to collagen production, cell proliferation, and migration. We further investigated the effect of epithelial-mesenchymal interaction on Stat3 in normal and keloid fibroblasts in noncoculture and coculture conditions. pY705 Stat3 was higher in keloid fibroblasts compared to normal fibroblasts in noncoculture. However, a more drastic decrease in pY705 Stat3 was observed in keloid fibroblasts compared to normal fibroblasts when cocultured with their respective keratinocytes over 5 days. To explore this paracrine effect, we examined the secretion of cytokines by cytokine arrays. Altered cytokine production was detected in keloid fibroblasts and keratinocytes, either in noncoculture or coculture conditions. IL-6, IL-8, monocyte chemoattractant protein-1, tissue inhibitor of metalloproteinases (TIMPs)-1, and TIMP-2 were major cytokines detected. Angiogenin, oncostatin M (OSM), vascular endothelial cell growth factor, IGF-binding protein-1, osteoprotegerin, and transforming growth factor-beta 2 were present in keloid keratinocyte-fibroblast coculture, but absent in normal keratinocyte-fibroblast coculture. Only IL-6 and OSM stimulated strong pY705 Stat3 and cell proliferation in both normal and keloid fibroblasts. Other cytokines increased proliferation of keloid fibroblasts, but not normal fibroblasts, suggesting an altered state in keloid fibroblasts. Multiple cytokines likely contribute to keloid pathogenesis and a combinatorial neutralizing antibody/cytokine therapy may be effective in ameliorating keloid scars.