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Induction of Notch signaling by tumor necrosis factor in rheumatoid synovial fibroblasts

Oncogene volume 22, pages 7796–7803 (2003)Cite this article

Abstract

Rheumatoid arthritis (RA) is characterized by progressive inflammation associated with abberrant proliferation of synoviocytes. In order to explore the characteristics of rheumatoid synovial fibroblasts (RSF), we performed the comparative gene expression profile analysis between RSF and normal synovial fibroblasts (NSF) upon tumor necrosis factor (TNF) stimulation. As an initial screening for the genes preferentially induced by TNF in RSF compared with NSF, we have adopted a cDNA array containing well-defined sets of genes responsible for cell growth, cell fate determination, and cellular invasiveness. Differentially expressed genes of interest were confirmed using real-time RT–PCR. We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues. The nucleus of RA synoviocytes showed strong staining with anti-Notch-1 and Notch-4 antibody. TNF induced the nuclear translocation of Notch intracellular domain in RSF, indicating the elicitation of the Notch signaling. Notch-1, Notch-4, and Jagged-2 proteins were also detected in the developing synovium of mouse embryo. Thus, RSF may have re-acquired the primordial phenotype, accounting for the hyperproliferation and aggressive invasiveness, exhibiting tumor-like phenotype.

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Abbreviations

RA:

rheumatoid arthritis

OA:

osteoarthritis

TNF:

tumor necrosis factor

IL-1β:

interleukin-1β

NF-ÎşB:

nuclear factor ÎşB

NICD:

Notch-1 intracellular domain

RBP-JÎş:

recombinant signal binding protein JÎş

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Acknowledgements

This work was supported by grants-in-aid from the Ministry of Health, Labor and Welfare (Grant No. H14-immunity-008), Ministry of Education, Culture, Sports, Science and Technology (Grant No. 14028052), and Japan Human Sciences Foundation (Grant No. SA14721).

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Authors and Affiliations

  1. Department of Molecular Genetics, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan

    Kiichiro Ando, Satoshi Kanazawa, Toshifumi Tetsuka, Shusuke Ohta, Xu Jiang & Takashi Okamoto

  2. Department of Orthopedics, Nagoya City University Medical School, Nagoya, 467-8601, Japan

    Kiichiro Ando, Shusuke Ohta, Xu Jiang, Masaaki Kobayashi & Nobuo Matsui

  3. Department of Pathology, Nagoya City University School of Nursing, Nagoya, 467-8601, Japan

    Toyohiro Tada

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  1. Kiichiro Ando
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  2. Satoshi Kanazawa
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Correspondence to Takashi Okamoto.

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Ando, K., Kanazawa, S., Tetsuka, T. et al. Induction of Notch signaling by tumor necrosis factor in rheumatoid synovial fibroblasts. Oncogene 22, 7796–7803 (2003). https://doi.org/10.1038/sj.onc.1206965

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