Differential inhibition of collagenase and interleukin-1alpha gene expression in cultured corneal fibroblasts by TGF-beta, dexamethasone, and retinoic acid.
Differential inhibition of collagenase and interleukin-1alpha gene expression in cultured corneal fibroblasts by TGF-beta, dexamethasone, and retinoic acid.
复制标题
DOI：
--
复制
发表时间：
1999-04
影响因子：
4.4
通讯作者：
J. West-Mays;James R. Cook;Peter M. Sadow;D. Mullady;Paola Bargagna-Mohan;K. Strissel;M. Fini
中科院分区：
文献类型：
--
作者：
J. West-Mays;James R. Cook;Peter M. Sadow;D. Mullady;Paola Bargagna-Mohan;K. Strissel;M. Fini
目的角膜损伤后，基质细胞被激活为修复成纤维细胞表型，诱导胶原酶和白细胞介素-1 α（IL-1 α）基因的表达。本研究检查了这些基因的表达被转化生长因子-β（TGF-β）、地塞米松（DEX）或视黄酸（RET A）抑制的机制。方法采用新鲜分离的角膜基质细胞和早期传代的角膜成纤维细胞培养模型。该模型再现了角膜伤口中基质细胞活化的事件。结果在角膜成纤维细胞早期传代培养中，胶原酶的表达受自分泌IL-1 α的强制性控制。IL-1 α通过依赖于转录因子NF-κ B的自分泌反馈环控制自身表达。TGF-β、DEX和RET A各自是这些细胞中胶原酶基因表达的有效抑制剂。此外，这些药物具有抑制IL-1 α表达的能力，这与它们影响NF-κ B的DNA结合活性的能力相关。然而，TGF-β、DEX和RET A也是不能表达IL-1 α的新鲜分离的角膜基质细胞表达的低水平胶原酶的有效抑制剂。结论：在具有活性IL-1 α自分泌环的细胞中，至少有两种不同的信号通路可以调节胶原酶基因的表达。本研究的结果表明，TGF-β，DEX和RET A差异抑制胶原酶和IL-1 α基因表达。这些信息将有助于设计角膜和眼睛其他部位纤维化疾病的治疗方式。
PURPOSE Expression of the genes for collagenase and interleukin-1alpha (IL-1alpha) are induced as stromal cells become activated to the repair fibroblast phenotype after injury to the cornea. This investigation examines the mechanisms whereby expression of these genes is inhibited by transforming growth factor-beta (TGF-beta), dexamethasone (DEX), or retinoic acid (RET A). METHODS A model of freshly isolated cultures of corneal stromal cells and early passage cultures of corneal fibroblasts was used in these studies. This model reproduces the events of stromal cell activation in the corneal wound. RESULTS In early passage cultures of corneal fibroblasts, expression of collagenase is under obligatory control by autocrine IL-1alpha. IL-1alpha controls its own expression through an autocrine feedback loop that is dependent on transcription factor NF-kappaB. TGF-beta, DEX, and RET A were each effective inhibitors of collagenase gene expression in these cells. Furthermore, these agents have the capacity to inhibit expression of IL-1alpha and this was correlated with their ability to affect DNA-binding activity of NF-kappaB. However, TGF-beta, DEX, and RET A were also effective inhibitors of the low level of collagenase expressed by freshly isolated corneal stromal cells that cannot express IL-1alpha. CONCLUSIONS In cells with an active IL-1alpha autocrine loop there are at least two distinct signaling pathways by which collagenase gene expression can be modulated. The results of this study demonstrate that TGF-beta, DEX, and RET A differentially inhibit collagenase and IL-1alpha gene expression. This information will be useful in the design of therapeutic modalities for fibrotic disease in the cornea and other parts of the eye.