Clark S D, Kobayashi D K, Welgus H G
Department of Medicine, Jewish Hospital, Washington University Medical Center, St. Louis, Missouri 63110.
J Clin Invest. 1987 Nov;80(5):1280-8. doi: 10.1172/JCI113203.
The regulation of the expression of interstitial collagenase and tissue inhibitor of metalloproteinases (TIMP) was examined in response to both retinoid compounds and glucocorticoids. Effective retinoids induced a dose-dependent, specific increase in the production of TIMP of approximately two- to threefold by monolayer cultures of human fibroblasts derived from various tissues, while simultaneously causing a decrease in collagenase secretion of similar magnitude. These effects were apparent by 8-12 h in culture and disappeared within 24 h after the withdrawal of retinoid compounds. The retinoid effect on TIMP production was mediated via an increased biosynthesis of new inhibitor protein. Similarly, increased steady state levels of TIMP messenger RNA (mRNA) accompanied by decreased quantities of collagenase mRNA were demonstrated, suggesting transcriptional control of the retinoid action. The data suggest that retinoids co-regulate the expression of collagenase and TIMP, and do so in an inverse manner. Dexamethasone caused a dose-dependent, specific decrease in collagenase production without altering the biosynthesis of TIMP. These findings were paralleled by a marked reduction in collagenase mRNA, without any accompanying change in TIMP mRNA. Therefore, TIMP and collagenase expression appear to be independently modulated by glucocorticoids.
研究了维甲酸化合物和糖皮质激素对间质胶原酶和金属蛋白酶组织抑制剂（TIMP）表达的调节作用。有效的维甲酸可使来自不同组织的人成纤维细胞单层培养物中TIMP的产生呈剂量依赖性、特异性增加，约为两到三倍，同时使胶原酶分泌量减少类似幅度。这些作用在培养8 - 12小时后明显，在撤去维甲酸化合物后24小时内消失。维甲酸对TIMP产生的作用是通过增加新抑制剂蛋白的生物合成介导的。同样，TIMP信使核糖核酸（mRNA）的稳态水平增加，同时胶原酶mRNA的量减少，这表明维甲酸作用存在转录调控。数据表明维甲酸共同调节胶原酶和TIMP的表达，且以相反的方式进行。地塞米松使胶原酶产生呈剂量依赖性、特异性减少，而不改变TIMP的生物合成。这些发现伴随着胶原酶mRNA的显著减少，而TIMP mRNA没有任何相应变化。因此，TIMP和胶原酶的表达似乎受到糖皮质激素的独立调节。
