Leiba M, Cahalon L, Shimoni A, Lider O, Zanin-Zhorov A, Hecht I, Sela U, Vlodavsky I, Nagler A
The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, and Sackler Medical School, Tel Aviv University, Isreal.
J Leukoc Biol. 2006 Aug;80(2):399-406. doi: 10.1189/jlb.0705409. Epub 2006 Jun 12.
Halofuginone, a low molecular weight plant alkaloid, inhibits collagen alpha1 (I) gene expression in several animal models and in patients with fibrotic disease, including scleroderma and graft-versus-host disease. In addition, halofuginone has been shown to inhibit angiogenesis and tumor progression. It was demonstrated recently that halofuginone inhibits transforming growth factor-beta (TGF-beta), an important immunomodulator. The present study was undertaken to explore the effects of halofuginone on activated T cells. Peripheral blood T cells were activated by anti-CD3 monoclonal antibodies in the absence and presence of halofuginone and assessed for nuclear factor (NF)-kappaB activity, production of tumor necrosis factor alpha (TNF-alpha) and interferon-gamma (IFN-gamma), T cell apoptosis, chemotaxis, and phosphorylation of p38 mitogen-activated protein kinase (MAPK). A delayed-type hypersensitivity (DTH) model was applied to investigate the effect of halofuginone on T cells in vivo. Preincubation of activated peripheral blood T cells with 10-40 ng/ml halofuginone resulted in a significant dose-dependent decrease in NF-kappaB activity (80% inhibition following incubation with 40 ng halofuginone, P = 0.002). In addition, 40 ng/ml halofuginone inhibited secretion of TNF-alpha, IFN-gamma, interleukin (IL)-4, IL-13, and TGF-beta (P < 0.005). Similarly, halofuginone inhibited the phosphorylation of p38 MAPK and apoptosis in activated T cells (P = 0.0001 and 0.005, respectively). In contrast, T cell chemotaxis was not affected. Halofuginone inhibited DTH response in mice, indicating suppression of T cell-mediated inflammation in vivo. Halofuginone inhibits activated peripheral blood T cell functions and proinflammatory cytokine production through inhibition of NF-kappaB activation and p38 MAPK phosphorylation. It also inhibited DTH response in vivo, making it an attractive immunomodulator and anti-inflammatory agent.
常山酮是一种低分子量植物生物碱，在多种动物模型以及包括硬皮病和移植物抗宿主病在内的纤维化疾病患者中，它可抑制胶原蛋白α1（I）基因的表达。此外，常山酮已被证明能抑制血管生成和肿瘤进展。最近有研究表明，常山酮可抑制转化生长因子-β（TGF-β），这是一种重要的免疫调节剂。本研究旨在探讨常山酮对活化T细胞的影响。在外周血T细胞被抗CD3单克隆抗体激活的情况下，分别在有和没有常山酮存在的条件下，评估其核因子（NF）-κB活性、肿瘤坏死因子α（TNF-α）和干扰素-γ（IFN-γ）的产生、T细胞凋亡、趋化性以及p38丝裂原活化蛋白激酶（MAPK）的磷酸化情况。应用迟发型超敏反应（DTH）模型来研究常山酮在体内对T细胞的作用。用10 - 40 ng/ml常山酮对活化的外周血T细胞进行预孵育，导致NF-κB活性显著剂量依赖性降低（与40 ng常山酮孵育后抑制率达80%，P = 0.002）。此外，40 ng/ml常山酮可抑制TNF-α、IFN-γ、白细胞介素（IL）-4、IL-13和TGF-β的分泌（P < 0.005）。同样，常山酮可抑制活化T细胞中p38 MAPK的磷酸化和凋亡（分别为P = 0.0001和0.005）。相反，T细胞趋化性未受影响。常山酮可抑制小鼠的DTH反应，表明其在体内可抑制T细胞介导的炎症。常山酮通过抑制NF-κB活化和p38 MAPK磷酸化来抑制活化的外周血T细胞功能和促炎细胞因子的产生。它还能在体内抑制DTH反应，使其成为一种有吸引力的免疫调节剂和抗炎剂。
