Schafer Peter H, Gandhi Anita K, Loveland Michelle A, Chen Roger S, Man Hon-Wah, Schnetkamp Paul P M, Wolbring Gregor, Govinda Sowmya, Corral Laura G, Payvandi Faribourz, Muller George W, Stirling David I
Celgene Corporation, 7 Powder Horn Dr., Warren, NJ 07059, USA.
J Pharmacol Exp Ther. 2003 Jun;305(3):1222-32. doi: 10.1124/jpet.102.048496. Epub 2003 Mar 20.
CC-4047 (Actimid) and CC-5013 (Revimid) belong to a class of thalidomide analogs collectively known as the immunomodulatory drugs (IMiDs), which are currently being assessed in the treatment of patients with multiple myeloma and other cancers. IMiDs potently enhance T cell and natural killer cell responses and inhibit tumor necrosis factor-alpha, interleukin (IL)-1 beta, and IL-12 production from LPS-stimulated peripheral blood mononuclear cells. However, the molecular mechanism of action for these compounds is unknown. Herein, we report on the ability of the IMiDs to up-regulate production of IL-2 from activated human CD4+ and CD8+ peripheral blood T cells, production of IL-2 and IFN-gamma from T helper (Th)1-type cells, and production of IL-5 and IL-10 from Th2-type cells. Elevation of IL-2 production from Jurkat T cells was observed as early as 6 h poststimulation and correlated with an increase in IL-2 promoter activity that was dependent upon the proximal but not the distal AP-1 binding site. The IMiDs enhanced AP-1-driven transcriptional activity 2- to 4-fold after 6 h of T cell stimulation, and their relative potencies for AP-1 activation correlated with their potencies for increased IL-2 production in Jurkat T cells and in CD4+ or CD8+ human peripheral blood T cells. The most potent of these IMiDs, CC-4047, had no effect on nuclear factor of activated T cells transcriptional activity, calcium signaling, or phosphorylation of extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase 1/2, p38 mitogen-activated protein kinase, or c-Jun/Jun D in Jurkat T cells. These data suggest that IMiDs increase T cell cytokine production by potentiating AP-1 transcriptional activity.
CC - 4047（来那度胺）和CC - 5013（泊马度胺）属于一类沙利度胺类似物，统称为免疫调节药物（IMiDs），目前正在对其治疗多发性骨髓瘤和其他癌症患者的效果进行评估。IMiDs能有效增强T细胞和自然杀伤细胞反应，并抑制脂多糖刺激的外周血单核细胞产生肿瘤坏死因子 - α、白细胞介素（IL） - 1β和IL - 12。然而，这些化合物的分子作用机制尚不清楚。在此，我们报告了IMiDs上调活化的人CD4⁺和CD8⁺外周血T细胞产生IL - 2的能力、辅助性T（Th）1型细胞产生IL - 2和干扰素 - γ的能力以及Th2型细胞产生IL - 5和IL - 10的能力。早在刺激后6小时就观察到Jurkat T细胞中IL - 2产生增加，且这与IL - 2启动子活性增加相关，该活性依赖于近端而非远端AP - 1结合位点。T细胞刺激6小时后，IMiDs使AP - 1驱动的转录活性增强2至4倍，它们激活AP - 1的相对效力与其在Jurkat T细胞以及CD4⁺或CD8⁺人外周血T细胞中增加IL - 2产生的效力相关。这些IMiDs中效力最强的CC - 4047对Jurkat T细胞中活化T细胞核因子的转录活性、钙信号传导或细胞外信号调节激酶1/2、c - Jun氨基末端激酶1/2、p38丝裂原活化蛋白激酶或c - Jun/Jun D的磷酸化均无影响。这些数据表明，IMiDs通过增强AP - 1转录活性来增加T细胞细胞因子的产生。
