Tsumura & Co., Tsumura Research Laboratories, Ibaraki, Japan.
Biol Pharm Bull. 2010;33(1):84-90. doi: 10.1248/bpb.33.84.
We investigated the association of interleukin-12 (IL-12) with development of dextran sulfate sodium (DSS)-induced colitis in mice, and examined the effects of TJN-419, a synthetic compound derived from acteoside, on this process. Enhanced IL-12 production in lipopolysaccharide (LPS)-stimulated macrophages was dose-dependently inhibited by addition of TJN-419 to culture medium, and this effect was abolished by pretreatment with PD98059, an inhibitor of extracellular-regulated kinase. We then assessed the effect of TJN-419 or a neutralizing antibody against murine IL-12 in a DSS-induced colitis model in C57 BL/6 mice. Colitis was induced by 5% DSS solution given as drinking water. Treatment with the anti-IL-12 antibody was performed intravenously and TJN-419 was administered orally. We also investigated the effect of TJN-419 on erosion in the rectum in a DSS-induced colitis model in rat. The IL-12 level in the rectum was significantly enhanced and the IL-10 level was significantly decreased in animals with DSS-induced colitis compared with untreated controls. Intravenous injection of the anti-IL-12 antibody and oral administration of TJN-419 inhibited clinical symptoms in DSS-induced colitis. TJN-419 also inhibited the increase in IL-12 and suppressed the area of erosion in the rectum in DSS-induced colitis in rats. These results indicate that IL-12 has a possible role in development of DSS-induced colitis and that TJN-419 is effective for treatment of this disease model via inhibition of IL-12 production.
我们研究了白细胞介素-12（IL-12）与葡聚糖硫酸钠（DSS）诱导的结肠炎在小鼠中的关联，并研究了 TJN-419（一种从獐牙菜苦苷衍生的合成化合物）对该过程的影响。TJN-419 可剂量依赖性地抑制脂多糖（LPS）刺激的巨噬细胞中 IL-12 的产生，而这种作用可被细胞外调节激酶抑制剂 PD98059 预处理所消除。然后，我们在 C57BL/6 小鼠的 DSS 诱导的结肠炎模型中评估了 TJN-419 或抗鼠 IL-12 中和抗体的作用。通过给予 5%DSS 溶液作为饮用水来诱导结肠炎。通过静脉内注射抗 IL-12 抗体和口服 TJN-419 进行治疗。我们还研究了 TJN-419 在 DSS 诱导的结肠炎大鼠模型中对直肠侵蚀的影响。与未处理的对照组相比，DSS 诱导的结肠炎动物的直肠中 IL-12 水平显著升高，IL-10 水平显著降低。静脉注射抗 IL-12 抗体和口服 TJN-419 抑制了 DSS 诱导的结肠炎的临床症状。TJN-419 还抑制了 IL-12 的增加，并抑制了 DSS 诱导的结肠炎大鼠直肠侵蚀面积的增加。这些结果表明，IL-12 可能在 DSS 诱导的结肠炎的发展中起作用，并且 TJN-419 通过抑制 IL-12 的产生对该疾病模型有效。
