转化生长因子-β1和糖皮质激素对人肺成纤维细胞和白血病细胞中肝细胞生长因子基因表达的负调控

Negative regulation of hepatocyte growth factor gene expression in human lung fibroblasts and leukemic cells by transforming growth factor-beta 1 and glucocorticoids.

作者信息

Matsumoto K, Tajima H, Okazaki H, Nakamura T

机构信息

Department of Biology, Faculty of Science, Kyushu University, Fukuoka, Japan.

出版信息

J Biol Chem. 1992 Dec 15;267(35):24917-20.

PMID:1459995

Abstract

Hepatocyte growth factor (HGF), a mesenchymal-derived factor which regulates growth, motility, and morphogenesis of epithelial and endothelial cells, functions as a hepatotrophic and renotrophic factor for regeneration of the liver and kidney. We have now obtained evidence that transforming growth factor-beta 1 (TGF-beta 1) and glucocorticoids are negative regulators for HGF gene expression. When TGF-beta 1 or dexamethasone was added to cultures of MRC-5 human embryonic lung fibroblasts and HL-60 human promyelocytic leukemic cells, the amount of HGF secreted into the culture medium was inhibited to 30-40% of that of control cultures by 10 ng/ml TGF-beta 1 and to 40-50% by 10(-6) M dexamethasone. The inhibitory effect of TGF-beta 1 and dexamethasone on HGF synthesis in MRC-5 cells was additive, thereby suggesting that TGF-beta 1 and dexamethasone exert effects through distinct mechanisms. Hydrocortisone also inhibited HGF synthesis with the same potency as dexamethasone; however, testosterone, estriol, and beta-estradiol had no effect. The rate of HGF synthesis in MRC-5 cells, as measured by pulse labeling with [35S]methionine and subsequent immunoprecipitation, was suppressed to 30-40% of the control with 10 ng/ml TGF-beta 1, and to 30-45% by 10(-6) M dexamethasone. HGF mRNA levels in MRC-5 cells and HL-60 cells were dose-dependently suppressed by TGF-beta 1 and dexamethasone; 10 ng/ml TGF-beta 1 suppressed HGF mRNA levels to 32% and 35% of control culture, respectively, in MRC-5 cells and HL-60 cells, and 10(-6) M dexamethasone suppressed to 43% and 38%, respectively. Thus, TGF-beta 1 and glucocorticoids seem to inhibit HGF synthesis by suppressing the expression of the HGF gene. We propose that a negative regulation of HGF gene expression by TGF-beta 1 or glucocorticoids may be involved in physiological or pathological processes during tissue regeneration.

摘要

肝细胞生长因子（HGF）是一种间充质来源的因子，可调节上皮细胞和内皮细胞的生长、运动及形态发生，作为肝营养因子和肾营养因子参与肝脏和肾脏的再生。我们现已获得证据表明，转化生长因子-β1（TGF-β1）和糖皮质激素是HGF基因表达的负调节因子。当将TGF-β1或地塞米松添加到MRC-5人胚肺成纤维细胞和HL-60人早幼粒细胞白血病细胞的培养物中时，分泌到培养基中的HGF量被10 ng/ml TGF-β1抑制至对照培养物的30%-40%，被10⁻⁶ M地塞米松抑制至40%-50%。TGF-β1和地塞米松对MRC-5细胞中HGF合成的抑制作用具有相加性，这表明TGF-β1和地塞米松通过不同机制发挥作用。氢化可的松也以与地塞米松相同的效力抑制HGF合成；然而，睾酮、雌三醇和β-雌二醇则无作用。通过用[³⁵S]甲硫氨酸脉冲标记并随后进行免疫沉淀测定，MRC-5细胞中HGF的合成速率被10 ng/ml TGF-β1抑制至对照的30%-40%，被10⁻⁶ M地塞米松抑制至30%-45%。MRC-5细胞和HL-60细胞中的HGF mRNA水平被TGF-β1和地塞米松剂量依赖性地抑制；10 ng/ml TGF-β1分别将MRC-5细胞和HL-60细胞中的HGF mRNA水平抑制至对照培养物的32%和35%，10⁻⁶ M地塞米松分别抑制至43%和38%。因此，TGF-β1和糖皮质激素似乎通过抑制HGF基因的表达来抑制HGF合成。我们提出，TGF-β1或糖皮质激素对HGF基因表达的负调节可能参与组织再生过程中的生理或病理过程。