Khalil Wajahat, Xia Hong, Bodempudi Vidya, Kahm Judy, Hergert Polla, Smith Karen, Peterson Mark, Parker Matthew, Herrera Jeremy, Bitterman Peter B, Henke Craig A
Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
Am J Respir Cell Mol Biol. 2015 Sep;53(3):391-9. doi: 10.1165/rcmb.2014-0150OC.
Idiopathic pulmonary fibrosis (IPF) is characterized by the relentless expansion of fibroblasts depositing type I collagen within the alveolar wall and obliterating the alveolar airspace. MicroRNA (miR)-29 is a potent regulator of collagen expression. In IPF, miR-29 levels are low, whereas type I collagen expression is high. However, the mechanism for suppression of miR-29 and increased type I collagen expression in IPF remains unclear. Here we show that when IPF fibroblasts are seeded on polymerized type I collagen, miR-29c levels are suppressed and type I collagen expression is high. In contrast, miR-29c is high and type I collagen expression is low in control fibroblasts. We demonstrate that the mechanism for suppression of miR-29 during IPF fibroblast interaction with polymerized collagen involves inappropriately low protein phosphatase (PP) 2A function, leading to histone deacetylase (HDA) C4 phosphorylation and decreased nuclear translocation of HDAC4. We demonstrate that overexpression of HDAC4 in IPF fibroblasts restored miR-29c levels and decreased type I collagen expression, whereas knocking down HDAC4 in control fibroblasts suppressed miR-29c levels and increased type I collagen expression. Our data indicate that IPF fibroblast interaction with polymerized type I collagen results in an aberrant PP2A/HDAC4 axis, which suppresses miR-29, causing a pathologic increase in type I collagen expression.
特发性肺纤维化（IPF）的特征是成纤维细胞在肺泡壁内持续扩张，沉积I型胶原蛋白并闭塞肺泡腔。微小RNA（miR）-29是胶原蛋白表达的有效调节因子。在IPF中，miR-29水平较低，而I型胶原蛋白表达较高。然而，IPF中miR-29受抑制和I型胶原蛋白表达增加的机制仍不清楚。在此我们表明，当将IPF成纤维细胞接种在聚合的I型胶原蛋白上时，miR-29c水平受到抑制，I型胶原蛋白表达较高。相反，对照成纤维细胞中miR-29c水平较高，I型胶原蛋白表达较低。我们证明，IPF成纤维细胞与聚合胶原蛋白相互作用期间miR-29受抑制的机制涉及蛋白磷酸酶（PP）2A功能异常低下，导致组蛋白脱乙酰酶（HDA）C4磷酸化以及HDAC4核转位减少。我们证明，在IPF成纤维细胞中过表达HDAC4可恢复miR-29c水平并降低I型胶原蛋白表达，而在对照成纤维细胞中敲低HDAC4则会抑制miR-29c水平并增加I型胶原蛋白表达。我们的数据表明，IPF成纤维细胞与聚合的I型胶原蛋白相互作用会导致异常的PP2A/HDAC4轴，该轴抑制miR-29，导致I型胶原蛋白表达病理性增加。
