Cyclin-dependent kinase inhibitor p21, via its C-terminal domain, is essential for resolution of murine inflammatory arthritis.
Cyclin-dependent kinase inhibitor p21, via its C-terminal domain, is essential for resolution of murine inflammatory arthritis.
复制标题
通过其C末端结构域，细胞周期蛋白依赖性激酶抑制剂P21对于解决鼠炎性关节炎至关重要。
DOI：
10.1002/art.33311
复制
发表时间：
2012-01
影响因子：
--
通讯作者：
Perlman, Harris
中科院分区：
文献类型：
--
作者：
Mavers, Melissa;Cuda, Carla M.;Misharin, Alexander V.;Gierut, Angelica K.;Agrawal, Hemant;Weber, Evan;Novack, Deborah Veis;Haines, G. Kenneth, III;Balomenos, Dimitrios;Perlman, Harris
类风湿性关节炎（RA）患者滑膜持续炎症的机制尚不清楚。此前，我们首次证明，与骨关节炎患者相比，RA患者滑膜组织中细胞周期蛋白依赖性激酶（CDK）抑制剂p21（WAF1/CIP1）的表达降低，并且p21是巨噬细胞炎症反应的新型抑制剂。在这里，我们试图确定 p21 介导的实验性炎症关节炎抑制的作用和机制。使用 K/BxN 血清转移诱导模型在 WT 或 p21−/− (C57BL/6) 小鼠中诱导实验性关节炎。将 p21 肽模拟物给予小鼠作为关节炎发展的预防剂。使用基于 Luminex 的测定、流式细胞术或 ELISA 在用 p21 肽模拟物处理的巨噬细胞中检查 LPS 诱导的细胞因子和信号转导途径。 p21−/−小鼠表现出实验性炎症性关节炎的增强和持续发展，这与巨噬细胞数量显着增加和严重的关节破坏有关。仅在 p21 完整小鼠中，施用 p21 肽模拟物可抑制巨噬细胞的活化并降低实验性关节炎的严重程度。从机制上讲，用 p21 肽模拟物处理会导致丝氨酸/苏氨酸激酶 Akt 的激活，并随后减少巨噬细胞中丝裂原激活蛋白激酶 p38 的激活亚型。这些数据首次揭示 p21 在限制 RA 等炎症性疾病中巨噬细胞的激活反应中发挥着重要作用。因此，针对巨噬细胞中的 p21 可能对于抑制 RA 的发展和持续存在至关重要。
The mechanism responsible for persistent inflammation of the synovium that occurs in patients with rheumatoid arthritis (RA) is unknown. Previously, we were the first to demonstrate that expression of the cyclin dependent kinase (CDK) inhibitor p21(WAF1/CIP1) is reduced in synovial tissue from RA patients compared to osteoarthritis patients and that p21 is a novel suppressor of the inflammatory response in macrophages. Here, we sought to determine the role and mechanism of p21-mediated suppression of experimental inflammatory arthritis. Experimental arthritis was induced in WT or p21−/− (C57BL/6) mice using the K/BxN serum transfer induced model. p21-peptide mimetics were administered to mice as a prophylactic for arthritis development. LPS-induced cytokine and signal transduction pathways were examined in macrophages that were treated with p21-peptide mimetics using Luminex-based assays, flow cytometry, or ELISAs. p21−/− mice exhibit enhanced and sustained development of experimental inflammatory arthritis, which is associated with markedly increased numbers of macrophages and severe articular destruction. Administration of a p21-peptide mimetic suppresses activation of macrophages and reduces the severity of experimental arthritis only in p21-intact mice. Mechanistically, treatment with the p21-peptide mimetic leads to activation of the serine/threonine kinase Akt and subsequent reduction in the activated isoform of mitogen-activated protein kinase p38 in macrophages. These data are the first to reveal that p21 plays an important role in limiting the activation response of macrophages in an inflammatory disease such as RA. Thus, targeting p21 in macrophages may be crucial for suppressing the development and persistence of RA.
登录
查看更多内容
影响因子：
3.9
作者：
Bresnihan, Barry;Pontifex, Eliza;Tak, Paul-Peter
通讯作者：
Tak, Paul-Peter
影响因子：
27.4
作者：
Polzer, K.;Baeten, D.;Zwerina, J.
通讯作者：
Zwerina, J.
影响因子：
4.8
作者：
Li, Y;Dowbenko, D;Lasky, LA
通讯作者：
Lasky, LA
影响因子：
4.4
作者：
Arias, Cristina F.;Ballesteros-Tato, Andre;Balomenos, Dimitrios
通讯作者：
Balomenos, Dimitrios
影响因子：
4.4
作者：
Goulvestre, C;Chéreau, C;Batteux, F
通讯作者：
Batteux, F