Peer Dan, Park Eun Jeong, Morishita Yoshiyuki, Carman Christopher V, Shimaoka Motomu
Immune Disease Institute and Department of Anesthesia, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Science. 2008 Feb 1;319(5863):627-30. doi: 10.1126/science.1149859.
Cyclin D1 (CyD1) is a pivotal cell cycle-regulatory molecule and a well-studied therapeutic target for cancer. Although CyD1 is also strongly up-regulated at sites of inflammation, its exact roles in this context remain uncharacterized. To address this question, we developed a strategy for selectively silencing CyD1 in leukocytes in vivo. Targeted stabilized nanoparticles (tsNPs) were loaded with CyD1-small interfering RNA (siRNA). Antibodies to beta(7) integrin (beta(7) I) were then used to target specific leukocyte subsets involved in gut inflammation. Systemic application of beta(7) I-tsNPs silenced CyD1 in leukocytes and reversed experimentally induced colitis in mice by suppressing leukocyte proliferation and T helper cell 1 cytokine expression. This study reveals CyD1 to be a potential anti-inflammatory target, and suggests that the application of similar modes of targeting by siRNA may be feasible in other therapeutic settings.
细胞周期蛋白D1（CyD1）是一种关键的细胞周期调节分子，也是一个经过充分研究的癌症治疗靶点。尽管CyD1在炎症部位也强烈上调，但其在这种情况下的确切作用仍不清楚。为了解决这个问题，我们开发了一种在体内选择性沉默白细胞中CyD1的策略。靶向稳定纳米颗粒（tsNPs）装载了CyD1小干扰RNA（siRNA）。然后使用β7整合素（β7I）抗体来靶向参与肠道炎症的特定白细胞亚群。全身应用β7I-tsNPs可使白细胞中的CyD1沉默，并通过抑制白细胞增殖和辅助性T细胞1细胞因子表达来逆转实验诱导的小鼠结肠炎。这项研究揭示CyD1是一个潜在的抗炎靶点，并表明在其他治疗环境中应用类似的siRNA靶向模式可能是可行的。
