JNK1, but Not JNK2, Is Required in Two Mechanistically Distinct Models of Inflammatory Arthritis
JNK1, but Not JNK2, Is Required in Two Mechanistically Distinct Models of Inflammatory Arthritis
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DOI：
10.1016/j.ajpath.2011.06.019
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发表时间：
2011-10-01
影响因子：
6
通讯作者：
Labuda, Tord
中科院分区：
文献类型：
--
作者：
Denninger, Katja;Rasmussen, Susanne;Labuda, Tord
c-Jun n末端激酶（JNKs）在炎性关节炎中的作用已被研究；然而，每种同型（即JNK1和JNK2）在类风湿关节炎中的作用以及是否抑制一种或两种对于改善疾病是必要的结论尚不清楚。通过在胶原诱导的关节炎中使用JNK1-或jnk2缺陷小鼠，以及在C57BL/6非肥胖糖尿病（K/BxN）血清转移性关节炎模型中使用KRN t细胞受体转基因小鼠，我们证明了JNK1缺乏对关节炎的保护作用，通过两种炎症性关节炎模型的临床评分和组织学评估来判断。相反，取消JNK2会加重疾病。在胶原诱导的关节炎中，JNK同型的独特作用至少部分可以通过JNK1-或jnk2缺陷巨噬细胞对微生物产物的反应中CD86表达的改变来解释，从而影响t细胞介导的免疫。Jnk1（-/-）小鼠对K/BxN血清诱导的关节炎的保护作用也可以用巨噬细胞功能低下来解释，因为野生型巨噬细胞过继转移到Jnk1（-/-）小鼠恢复了疾病易感性。因此，我们的研究结果为广泛的JNK抑制剂的适度治疗效果提供了可能的解释，并建议未来的治疗应该选择性地靶向JNK1亚型。（蚂蚁病理学杂志，2011,179:1884-1893,DOI: 10.1016/ j.j ajpath.2011.06.019）
The roles of the c-Jun N-terminal kinases (JNKs) in inflammatory arthritis have been investigated; however, the roles of each isotype (ie, JNK1 and JNK2) in rheumatoid arthritis and conclusions about whether inhibition of one or both is necessary for amelioration of disease are unclear. By using JNK1- or JNK2-deficient mice in the collagen-induced arthritis and the KRN T-cell receptor transgenic mouse on C57BL/6 nonobese diabetic (K/BxN) serum transfer arthritis models, we demonstrate that JNK1 deficiency results in protection from arthritis, as judged by clinical score and histological evaluation in both models of inflammatory arthritis. In contrast, abrogation of JNK2 exacerbates disease. In collagen-induced arthritis, the distinct roles of the JNK isotypes can, at least in part, be explained by altered regulation of CD86 expression in JNK1- or JNK2-deficient macrophages in response to microbial products, thereby affecting T-cell-mediated immunity. The protection from K/BxN serum-induced arthritis in Jnk1(-/-) mice can also be explained by inept macrophage function because adoptive transfer of wild-type macrophages to Jnk1(-/-) mice restored disease susceptibility. Thus, our results provide a possible explanation for the modest therapeutic effects of broad JNK inhibitors and suggest that future therapies should selectively target the JNK1 isoform. (Ant J Pathol 2011, 179:1884-1893, DOI: 10.1016/j.ajpath.2011.06.019)