Assi Kiran, Pillai Rex, Gómez-Muñoz Antonio, Owen David, Salh Baljinder
The Jack Bell Research Centre, Vancouver, BC, Canada.
Immunology. 2006 May;118(1):112-21. doi: 10.1111/j.1365-2567.2006.02349.x.
Stress-activated protein kinases (SAPKs) are activated in human inflammatory bowel disease (IBD). Recently it has been demonstrated that p38MAPK (mitogen-activated protein kinase) inhibition using SB203580 is effective in reducing disease in both dextran sulphate sodium (DSS)-induced and 2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced murine colitides, underscoring the importance of this pathway in gastrointestinal inflammation. However, the contribution of c-Jun N-terminal kinase (JNK) in intestinal inflammation is unknown. Based on the known involvement of JNK in tumour necrosis factor-alpha (TNF-alpha) expression and in mediating the effects of oxidant stress, we hypothesized that JNK inhibition would also affect colitis. Our studies in mice with DSS-induced colitis treated with the JNK inhibitor SP600125, indicate that there is a significant reduction in wasting as well as a significant reduction in histological damage scores. Both total colonic and mesenteric lymphocyte CD3/CD28-stimulated TNF-alpha levels were dramatically reduced under the same circumstances. This was associated with a reduction in JNK protein expression and activity, as well as a reduction in AP-1 DNA binding with SP600125. Interestingly, there were no apparent changes in either p38MAPK or p42/44ERKs. Immunofluorescence of the colon for the active form of JNK revealed a prominent signal arising from the infiltrating inflammatory cells. SP600125 reduced this as well as, specifically, macrophage infiltration. Strikingly, we also demonstrate reduced epithelial cell apoptosis in response to treatment with SP600125. We conclude that specific inhibition of JNK is beneficial in the DSS model of colitis, and may be of value in human IBD.
应激激活蛋白激酶（SAPKs）在人类炎症性肠病（IBD）中被激活。最近有研究表明，使用SB203580抑制p38丝裂原活化蛋白激酶（p38MAPK）可有效减轻葡聚糖硫酸钠（DSS）诱导和2,4,6-三硝基苯磺酸（TNBS）诱导的小鼠结肠炎，强调了该信号通路在胃肠道炎症中的重要性。然而，c-Jun氨基末端激酶（JNK）在肠道炎症中的作用尚不清楚。基于JNK在肿瘤坏死因子-α（TNF-α）表达及介导氧化应激效应中的已知作用，我们推测抑制JNK也会影响结肠炎。我们对用JNK抑制剂SP600125治疗的DSS诱导的结肠炎小鼠进行的研究表明，体重减轻显著减少，组织学损伤评分也显著降低。在相同情况下，结肠和肠系膜淋巴细胞经CD3/CD28刺激后的TNF-α水平均显著降低。这与JNK蛋白表达和活性降低以及SP600125处理后AP-1与DNA结合减少有关。有趣的是，p38MAPK或p42/44细胞外信号调节激酶（p42/44ERKs）均无明显变化。对结肠中活性形式的JNK进行免疫荧光检测，发现浸润的炎症细胞发出明显信号。SP600125可减少这种信号，特别是巨噬细胞浸润。令人惊讶的是，我们还证明，SP600125处理可减少上皮细胞凋亡。我们得出结论，特异性抑制JNK对结肠炎的DSS模型有益，可能对人类IBD有价值。
