期刊
RHEUMATOLOGY
卷 54, 期 1, 页码 178-187出版社
OXFORD UNIV PRESS
DOI: 10.1093/rheumatology/keu279
关键词
rheumatoid arthritis; methotrexate; Jun-N-terminal kinase; p53; nuclear factor-kappaB; T cell; fibroblast-like synoviocytes
类别
资金
- National Institutes of Health [R21AR063846, R42AI53948, R01AI044924]
- American College of Rheumatology Within Our Reach grant program [ACR124405]
- National Center for Advancing Translation Sciences [UL1TR000445]
- National Science Foundation Graduate Research Fellowship Program
Methods. An NF-kappa B luciferase reporter plasmid was used to measure NF-kappa B activation across experimental stimuli. Flow cytometry was used to quantify changes in intracellular protein levels, measure levels of reactive oxygen species and determine apoptosis. Quantitative RT-PCR was used to identify changes in MTX target genes. Results. In T cell lines, MTX (0.1 mu M) inhibited activation of NF-kappa B via depletion of tetrahydrobiopterin (BH4) and increased Jun-N-terminal kinase (JNK)-dependent p53 activity. Inhibitors of BH4 activity or synthesis also inhibited NF-kappa B activation and, similar to MTX, increased JNK, p53, p21 and JUN activity. Patients with RA expressed increased levels of phosphorylated or active RelA (p65) compared with controls. Levels of phosphorylated RelA were reduced in patients receiving low-dose MTX therapy. In contrast, inhibition of NF-kappa B activation by MTX was not mediated via BH4 depletion and JNK activation in FLSs, but rather was completely prevented by adenosine receptor antagonists. Conclusion. Our findings support a model whereby distinct pathways are activated by MTX in T cells and FLSs to inhibit NF-kappa B activation.
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