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Abstract Number: 418

Immediate Early Response Gene X-1 Is Over-Expressed and Regulates Apoptosis and Cytokine Production in Rheumatoid Arthritis Synovial Fibroblasts

Akio Morinobu1, Masaaki Fujita2, Shino Tanaka3, Jun Saegusa4 and Shunichi Kumagai5, 1Department of clinical pathology and immunology, Kobe university graduate school of medicine, Kobe 650-0017, Japan, 2Kobe University Graduate School of Medicine, Kobe, Japan, 3Department of Clinical Pathology and Immunology, Rheumatology and Clinical Immunology, Kobe, Japan, 4Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan, 5Center of rheumatic diseases, Shinko hospital, Kobe, Japan

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Apoptosis, cytokines and rheumatoid arthritis, synovium

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Session Information

Title: Rheumatoid Arthritis - Human Etiology and Pathogenisis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Histone deacetylase inhibitors (HDACi) are potential therapeutic drugs for the treatment of rheumatoid arthritis (RA). We found that an HDACi up-regulates the gene expression of immediate early response gene X-1 (IEX-1) in rheumatoid arthritis synovial fibroblasts (RA-SF). IEX-1 is regulated by various stress stimuli and involved in apoptosis and cell growth. Since the role of IEX-1 has never been examined in RA, we examined the expression and function of the molecule in RA-SF.

Methods: Synovial fibroblasts from RA and OA patients were cultured and used between 2-4 passages. Gene and protein expression was determined by qPCR and Western blotting, respectively. Apoptosis was detected by annexin V staining using a flow cytometer. To examine the function of IEX-1, IEX-1 was knocked down by siRNA or over-expressed with lipofection.

Results: (1) IEX-1 mRNA levels were higher in RA-SF than in OA-SF. LPS and TNFa up-regulated the IEX-1 mRNA expression in RA-SF. (2)Over-expression of IEX-1 induced apoptosis and promoted anti-Fas mAb-mediated apoptosis in RA-SF, while knockdown of IEX-1 protected RA-SF from anti-Fas mAb-mediated apoptosis. Also, over-expression of IEX-1 augmented anti-Fas mAb-induced caspase-8 activation, while knockdown of IEX-1 suppressed it. Thus, IEX-1 promotes anti-Fas mAb-induced apoptosis through up-regulating caspase-8 activity. (3) IEX-1 was up-regulated by TSA, an HDACi.  Interestingly, apoptosis induced by TSA plus anti-Fas mAb in RA-SF was partially inhibited by knockdown of IEX-1, indicating that TSA-induced apoptosis was mediated, at least in part, by the up-regulation of IEX-1. (3)When IEX-1 expression was down-regulated with siRNA, LPS-induced IL-6 production was decreased, showing that IEX-1 is also involved in cytokine production from RA-SF.

Conclusion: IEX-1 is over-expressed in RA-SF and further induced by TNFa. IEX-1 facilitates anti-Fas mAb-induced apoptosis by enhancing caspase activation, and regulates cytokine production. IEX-1 is likely to play an important role in RA pathogenesis.


Disclosure:

A. Morinobu,
None;

M. Fujita,
None;

S. Tanaka,
None;

J. Saegusa,
None;

S. Kumagai,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/immediate-early-response-gene-x-1-is-over-expressed-and-regulates-apoptosis-and-cytokine-production-in-rheumatoid-arthritis-synovial-fibroblasts/

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