You Xin, Pan Meng, Gao Wenli, Shiah Her-Shyong, Tao Jian, Zhang Dongqing, Koumpouras Fotios, Wang Shuang, Zhao Hongyu, Madri Joseph A, Baker David, Cheng Yung-Chi, Yin Zhinan
Yale University, New Haven, Connecticut 06520-8031, USA.
Arthritis Rheum. 2006 Mar;54(3):877-86. doi: 10.1002/art.21640.
To test the effects of a novel tylophorine analog, DCB 3503, on the prevention and treatment of collagen-induced arthritis (CIA) and to elucidate its underlying mechanisms.
DBA/1J mice were immunized with type II collagen, and in some cases, lipopolysaccharide (LPS) was used to boost the development of arthritis. DCB 3503 was injected intraperitoneally before or after the onset of CIA. Mice were monitored to assess the effects of DCB 3503 on the clinical severity of the disease, and pathologic changes in the joints were examined histologically. Levels of tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta) in serum and joint tissues were measured by enzyme-linked immunosorbent assay and by cytometric bead array analysis. The effect of DCB 3503 on LPS-induced proinflammatory cytokines from bone marrow-derived dendritic cells was determined by flow cytometry.
DCB 3503 significantly suppressed the development and progression of CIA. Moreover, DCB 3503 completely blocked the LPS-triggered acceleration of joint inflammation and destruction. Consistent with its effects in vivo, DCB 3503 significantly suppressed the synthesis of proinflammatory cytokines in inflamed joints as well as cytokine synthesis by macrophages examined ex vivo. Treatment also reduced the levels of inflammatory cytokines (IL-6, IL-12, TNFalpha, and monocyte chemotactic protein 1) produced by bone marrow-derived dendritic cells in vitro. However, DCB 3503 showed no direct effects on T cell proliferation and B cell antibody response.
Because of its ability to specifically suppress innate immune responses, DCB 3503 may be a novel therapeutic agent for inflammatory arthritis in humans.
测试新型娃儿藤碱类似物DCB 3503对胶原诱导性关节炎（CIA）的预防和治疗效果，并阐明其潜在机制。
用II型胶原免疫DBA/1J小鼠，在某些情况下，使用脂多糖（LPS）促进关节炎的发展。在CIA发病前或发病后腹腔注射DCB 3503。监测小鼠以评估DCB 3503对疾病临床严重程度的影响，并通过组织学检查关节的病理变化。通过酶联免疫吸附测定和细胞计数珠阵列分析测量血清和关节组织中肿瘤坏死因子α（TNFα）和白细胞介素-1β（IL-1β）的水平。通过流式细胞术确定DCB 3503对LPS诱导的骨髓来源树突状细胞促炎细胞因子的影响。
DCB 3503显著抑制CIA的发展和进展。此外，DCB 3503完全阻断了LPS引发的关节炎症和破坏的加速。与其体内作用一致，DCB 3503显著抑制炎症关节中促炎细胞因子的合成以及体外检测的巨噬细胞的细胞因子合成。治疗还降低了体外骨髓来源树突状细胞产生的炎性细胞因子（IL-6、IL-12、TNFα和单核细胞趋化蛋白1）的水平。然而，DCB 3503对T细胞增殖和B细胞抗体反应没有直接影响。
由于DCB 3503能够特异性抑制先天性免疫反应，它可能是一种治疗人类炎性关节炎的新型治疗药物。
