Cyclin-dependent kinase inhibitor p21, via its C-terminal domain, is essential for resolution of murine inflammatory arthritis

被引:37
作者
Mavers, Melissa [2 ]
Cuda, Carla M.
Misharin, Alexander V.
Gierut, Angelica K.
Agrawal, Hemant
Weber, Evan
Novack, Deborah Veis [3 ]
Haines, G. Kenneth, III [4 ]
Balomenos, Dimitrios [5 ]
Perlman, Harris [1 ]
机构
[1] Northwestern Univ, Feinberg Sch Med, Dept Med Rheumatol, Chicago, IL 60611 USA
[2] St Louis Univ, Sch Med, St Louis, MO USA
[3] Washington Univ, Sch Med, St Louis, MO USA
[4] Yale Univ, Sch Med, New Haven, CT USA
[5] CSIC, Ctr Nacl Biotecnol, Madrid, Spain
来源
ARTHRITIS AND RHEUMATISM | 2012年 / 64卷 / 01期
关键词
SYSTEMIC-LUPUS-ERYTHEMATOSUS; COLLAGEN-INDUCED ARTHRITIS; NF-KAPPA-B; RHEUMATOID-ARTHRITIS; MACROPHAGE ACTIVATION; THERAPEUTIC INTERVENTION; CELL-SURVIVAL; GENE; EXPRESSION; PROLIFERATION;
D O I
10.1002/art.33311
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective 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. Methods. 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 sig-nal transduction pathways in macrophages that were treated with p21 peptide mimetics were examined by Luminex-based assay, flow cytometry, or enzyme-linked immunosorbent assay. Results. 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. Conclusion. 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.
引用
收藏
页码:141 / 152
页数:12
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