Department of Dermatology, XiangYa Hospital, Central South University, Changsha, Hunan, People's Republic of China.
J Dermatol Sci. 2013 Jun;70(3):182-9. doi: 10.1016/j.jdermsci.2013.02.005. Epub 2013 Feb 28.
Methotrexate (MTX) is a drug used to treat psoriasis due to inducing immune cell apoptosis. However, certain patients show MTX resistant. CD147, highly expressed by psoriatic PBMCs, is assumed to regulate MTX sensitivity. The underlining mechanism is still relatively understudied.
To understand the mechanisms of that CD147 promotes MTX resistance in immune cells.
The expression of CD147 and ABCG2 in PBMCs from psoriatic patients, cellular apoptosis and intracellular MTX amount were measured. We also checked the cellular drug sensitivity of CHO (Chinese Hamster Ovary) cell lines with introduced CD147 and Jurkat T cells depeleted CD147. By immunoprecipitation, we detected the interaction between CD147 and ABCG2.
Both ABCG2 and CD147 are highly expressed in psoriatic PBMCs. Cultured in vitro, the PBMCs from psoriatic patients were more resistant to MTX-induced apoptosis comparing to PBMCs from healthy people. Further studies demonstrated that exogenous overexpression of CD147 in CHO cells increased ABCG2 protein level. After MTX treatment, CD147 overexpressing CHO cells showed lower apoptosis rate and lower intracellular MTX concentration. On the contrary, knockdown of CD147 by shRNA in Jurkat T cells decreased ABCG2 expression, as well as increased MTX-induced apoptosis and decreased MTX efflux. Immunoprecipitation experiment revealed that the trans-membrane domain of CD147 conferred its' interaction with ABCG2.
Our study suggests a role of CD147 in regulating ABCG2 transportation of MTX in immune cells. Strategies involving targeting CD147 could be considered in clinical treatment of psoriatic patients resistant to MTX.
甲氨蝶呤（MTX）是一种用于治疗银屑病的药物，因为它可以诱导免疫细胞凋亡。然而，某些患者表现出 MTX 耐药性。CD147 在银屑病患者的 PBMC 中高度表达，被认为可以调节 MTX 敏感性。其潜在机制仍相对研究不足。
了解 CD147 如何促进免疫细胞中甲氨蝶呤的耐药性。
检测银屑病患者 PBMC 中 CD147 和 ABCG2 的表达、细胞凋亡和细胞内 MTX 含量。我们还检查了转染 CD147 的 CHO（中国仓鼠卵巢）细胞系和耗尽 CD147 的 Jurkat T 细胞的细胞药物敏感性。通过免疫沉淀检测 CD147 和 ABCG2 之间的相互作用。
ABCG2 和 CD147 在银屑病患者的 PBMC 中均高度表达。体外培养时，与健康人 PBMC 相比，银屑病患者的 PBMC 对 MTX 诱导的凋亡更具耐药性。进一步的研究表明，CHO 细胞中外源过表达 CD147 会增加 ABCG2 蛋白水平。用 MTX 处理后，CD147 过表达的 CHO 细胞的凋亡率较低，细胞内 MTX 浓度较低。相反，用 shRNA 敲低 Jurkat T 细胞中的 CD147 会降低 ABCG2 的表达，同时增加 MTX 诱导的凋亡并减少 MTX 外排。免疫沉淀实验表明，CD147 的跨膜结构域赋予其与 ABCG2 的相互作用。
本研究提示 CD147 在调节免疫细胞中甲氨蝶呤的 ABCG2 转运中起作用。针对 CD147 的策略可考虑用于治疗对 MTX 耐药的银屑病患者。
