Sunman Jeffrey A, Hawke Roy L, LeCluyse Edward L, Kashuba Angela D M
School of Pharmacy, Division of Pharmacotherapy, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599-7360, USA.
Drug Metab Dispos. 2004 Mar;32(3):359-63. doi: 10.1124/dmd.32.3.359.
Interleukin (IL)-2 administration has been shown to decrease CYP3A enzyme activity in vivo. To determine whether IL-2 suppression of human hepatocyte CYP3A activity is direct or whether it is facilitated by the presence of Kupffer cells, primary human hepatocytes were cultured alone or cocultured with primary human Kupffer cells at physiologic hepatocyte/Kupffer cell ratios of 10:1 or 10:4. Using proinflammatory cytokines as positive controls, IL-1 (0.2-20 ng/ml) and IL-6 (2-200 ng/ml) exposure resulted in a 70 to 90% decrease in CYP3A activity after 72 h in hepatocyte cultures. In the hepatocyte/Kupffer cell cocultures, an 80% decrease in CYP3A activity was observed with IL-1 (2 ng/ml) or IL-6 (20 ng/ml), suggesting that direct suppressive effects of proinflammatory cytokines on hepatocyte CYP3A activity are not substantially altered by Kupffer cells. In contrast to the effects of these proinflammatory cytokines, no sustained suppression of CYP3A activity was observed with IL-2 (2-200 ng/ml) in hepatocyte cultures. However, in hepatocyte/Kupffer cell cocultures, a concentration-dependent 50 to 70% suppression of CYP3A activity was observed with IL-2 at 72 h. In summary, these data suggest that Kupffer cells are required to reconstitute the suppressive effects of IL-2 on CYP3A activity that are observed in vivo and that hepatocyte/Kupffer cell cocultures may provide a useful model for investigating mechanisms of CYP3A4 regulation by cytokines. Of particular relevance to certain hepatic diseases, these findings suggest potential mechanisms whereby cytokines released from infiltrating blood mononuclear cells might modulate intercellular signaling and controls on hepatocyte function by various cell types that reside in liver.
已证明体内给予白细胞介素（IL）-2可降低CYP3A酶活性。为了确定IL-2对人肝细胞CYP3A活性的抑制是直接作用，还是由库普弗细胞的存在所促成，将原代人肝细胞单独培养，或以10:1或10:4的生理肝细胞/库普弗细胞比例与原代人库普弗细胞共培养。以促炎细胞因子作为阳性对照，在肝细胞培养物中，暴露于IL-1（0.2 - 20 ng/ml）和IL-6（2 - 200 ng/ml）72小时后，CYP3A活性降低了70%至90%。在肝细胞/库普弗细胞共培养物中，观察到IL-1（2 ng/ml）或IL-6（20 ng/ml）使CYP3A活性降低了80%，这表明促炎细胞因子对肝细胞CYP3A活性的直接抑制作用不会因库普弗细胞而发生实质性改变。与这些促炎细胞因子的作用相反，在肝细胞培养物中，未观察到IL-2（2 - 200 ng/ml）对CYP3A活性的持续抑制。然而，在肝细胞/库普弗细胞共培养物中，72小时时观察到IL-2对CYP3A活性有浓度依赖性的50%至70%的抑制作用。总之，这些数据表明，库普弗细胞是在体内观察到的IL-2对CYP3A活性抑制作用得以重建所必需的，并且肝细胞/库普弗细胞共培养物可能为研究细胞因子对CYP3A4调控机制提供一个有用的模型。与某些肝脏疾病特别相关的是，这些发现提示了潜在的机制，即浸润的血液单核细胞释放的细胞因子可能通过多种驻留在肝脏中的细胞类型来调节细胞间信号传导并控制肝细胞功能。
