Mavers Melissa, Cuda Carla M, Misharin Alexander V, Gierut Angelica K, Agrawal Hemant, Weber Evan, Novack Deborah Veis, Haines G Kenneth, Balomenos Dimitrios, Perlman Harris
Saint Louis University School of Medicine, St. Louis, Missouri, USA.
Arthritis Rheum. 2012 Jan;64(1):141-52. doi: 10.1002/art.33311.
The mechanism responsible for persistent synovial inflammation in rheumatoid arthritis (RA) is unknown. Previously, we demonstrated that expression of the cyclin-dependent kinase inhibitor p21 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. The present study was undertaken to investigate the role and mechanism of p21-mediated suppression of experimental inflammatory arthritis.
Experimental arthritis was induced in wild-type or p21-/- (C57BL/6) mice, using the K/BxN serum-transfer model. Mice were administered p21 peptide mimetics as a prophylactic for arthritis development. Lipopolysaccharide-induced cytokine and signal transduction pathways in macrophages that were treated with p21 peptide mimetics were examined by Luminex-based assay, flow cytometry, or enzyme-linked immunosorbent assay.
Enhanced and sustained development of experimental inflammatory arthritis, associated with markedly increased numbers of macrophages and severe articular destruction, was observed in p21-/- mice. Administration of a p21 peptide mimetic suppressed activation of macrophages and reduced the severity of experimental arthritis in p21-intact mice only. Mechanistically, treatment with the p21 peptide mimetic led to activation of the serine/threonine kinase Akt and subsequent reduction of the activated isoform of p38 MAPK in macrophages.
These are the first reported data to reveal that p21 has a key 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.
类风湿关节炎（RA）中持续性滑膜炎的发病机制尚不清楚。此前，我们发现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抑制剂p21的表达降低，并且p21是巨噬细胞炎症反应的新型抑制剂。本研究旨在探讨p21介导的实验性炎症性关节炎抑制作用的作用及机制。
使用K/BxN血清转移模型在野生型或p21基因敲除（C57BL/6）小鼠中诱导实验性关节炎。给小鼠施用p21肽模拟物作为关节炎发展的预防性药物。通过基于Luminex的检测、流式细胞术或酶联免疫吸附测定法检测用p21肽模拟物处理的巨噬细胞中脂多糖诱导的细胞因子和信号转导途径。
在p21基因敲除小鼠中观察到实验性炎症性关节炎的增强和持续发展，伴有巨噬细胞数量明显增加和严重的关节破坏。仅在p21基因完整的小鼠中，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肽模拟物处理导致丝氨酸/苏氨酸激酶Akt活化，并随后降低巨噬细胞中p38 MAPK的活化异构体水平。
这些是首次报道的数据，揭示了p21在限制诸如RA等炎症性疾病中巨噬细胞的活化反应中起关键作用。因此，针对巨噬细胞中的p21可能对抑制RA的发展和持续存在至关重要。
