Generation and characterization of p38β (MAPK11) gene-targeted mice
Generation and characterization of p38β (MAPK11) gene-targeted mice
复制标题
DOI：
10.1128/mcb.25.23.10454-10464.2005
复制
发表时间：
2005-12-01
影响因子：
5.3
通讯作者：
Arthur, JSC
中科院分区：
文献类型：
--
作者：
Beardmore, VA;Hinton, HJ;Arthur, JSC
p38丝裂原活化蛋白激酶（MAPKs）主要在炎症细胞因子和细胞应激反应中被激活，靶向p38 α和p38 β MAPKs的抑制剂已显示出治疗炎症性疾病的潜力。在这里，我们报告了p38 β (MAPK11)基因敲除的产生和初步表征。P38 β(-/-)小鼠存活，无明显健康问题。p38 β(-/-)小鼠胚胎成纤维细胞中p38 α、ERK1/2和JNK在细胞应激下的表达和激活是正常的，p38活化激酶MAPKAP-K2和MSK1的激活也是正常的。p38依赖性即刻早期基因的转录也不受p38 β敲除的影响，这表明p38 α是参与这些过程的主要亚型。p38 β(-/-)小鼠也显示出正常的t细胞发育。脂多糖诱导的细胞因子产生在p38 β(-/-)小鼠中也是正常的。由于p38被肿瘤坏死因子激活，将p38 β(-/-)小鼠杂交到TNF δ ARE小鼠系上。这些小鼠过度表达肿瘤坏死因子，导致类似类风湿性关节炎和炎症性肠病的发展症状。然而，p38 β基因敲除并不能减缓这些疾病的进展。综上所述，这些结果表明p38a，而不是p38 β，是参与免疫反应的主要p38亚型，并且在p38抑制剂的开发过程中，不需要保持对p38 β的活性。
p38 mitogen-activated protein kinases (MAPKs) are activated primarily in response to inflammatory cytokines and cellular stress, and inhibitors which target the p38 alpha and p38 beta MAPKs have shown potential for the treatment of inflammatory disease. Here we report the generation and initial characterization of a knockout of the p38 beta (MAPK11) gene. p38 beta(-/-) mice were viable and exhibited no apparent health problems. The expression and activation of p38 alpha, ERK1/2, and JNK in response to cellular stress was normal in embryonic fibroblasts from p38 beta(-/-) mice, as was the activation of p38-activated kinases MAPKAP-K2 and MSK1. The transcription of p38-dependent immediate-early genes was also not affected by the knockout of p38 beta, suggesting that p38 alpha is the predominant isoform involved in these processes. The p38 beta(-/-) mice also showed normal T-cell development. Lipopolysaccharide-induced cytokine production was also normal in the p38 beta(-/-) mice. As p38 is activated by tumor necrosis factor, the p38 beta(-/-) mice were crossed onto a TNF Delta ARE mouse line. These mice overexpress tumor necrosis factor, which results in development symptoms similar to rheumatoid arthritis and inflammatory bowel disease. The progression of these diseases was not however moderated by knockout of p38 beta. Together these results suggest that p38a, and not p38 beta, is the major p38 isoform involved in the immune response and that it would not be necessary to retain activity against p38 beta during the development of p38 inhibitors.