Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.


Overexpression of Tristetraprolin Regulates Collagen Induced Arthritis

Jingu1,  Takashi, Suzuki1,  Takeshi, Sugihara1,  Makoto, Suzuki2,  Eiji, Kondo1,  Yuya, Matsumoto1,  Isao, Hayashi1,  Taichi

University of Tsukuba, Tsukuba, Japan
Ohta-Nishinouchi Hospital, Koriyama, Japan
Takikawa city hospital, Takikawa, Japan

Purpose:

Tristetraprolin (TTP) is a widely expressed protein with two zinc finger domains that act as active RNA-binding sites. TTP is an immediate early response gene expressed in fibroblasts and other cells upon induction by a variety of stimuli. TTP is posttranscriptional regulation molecule that downregulates tumor necrosis factor-a (TNF-a) production by binding to AU-rich element on TNF-a mRNA, and promoting TNF-a mRNA degradation. TTP-knockout mice display an inflammatory phenotype characterized by inflammatory arthritis, dermatitis, cachexia, autoimmunity, and myeloid hyperplasia and this phenotype can be prevented by administration of anti-TNF-a antibodies. We developed transgenic mice overexpressing zinc finger (ZF-Tg DBA/1 mice), a part of TTP, and investigated TTP mRNA expression in several organs, TNF-a mRNA stability, and production by lipopolysaccharide (LPS) stimulation in vitro. Furthermore, we examined the development of collagen induced arthritis (CIA) in vivo.

Method:

(1) We investigated TTP mRNA distribution in joint, muscle, heart, thymus, lung, liver, small intestine, colon, spleen, and inguinal lymph nodes of ZF-Tg DBA/1 mice by RT-PCR. (2) We investigated TTP mRNA stability in the splenocytes of ZF-Tg DBA/1 mice. (3) We investigated TNF-a production in splenocytes of ZF-Tg DBA/1 mice after LPS stimulation by ELISA. (4) We induced CIA by immunization of type II collagen to DBA/1 mice and ZF-Tg DBA/1 mice at twice (day 0 and day 21), and monitored the clinical score of arthritis.

Results:

(1) TTP-ZF transgene mRNA was expressed in these all tissues. (2) TNF-a mRNA in ZF-Tg DBA/1 mice was more instable than DBA/1 mice. (3) TNF-a production in ZF-Tg DBA/1 mice was more decreased than DBA/1 mice. (4) The clinical score of arthritis in ZF-Tg DBA/1 mice was significantly suppressed.

Conclusion:

We identified that the overexpression of zinc finger part of TTP caused the instability of TNF-a mRNA and the downregulation of TNF-a production, and resulting in the suppression of CIA. These findings open a new strategy for the regulation of autoimmune arthritis through TTP induction.

To cite this abstract, please use the following information:
Jingu, Takashi, Suzuki, Takeshi, Sugihara, Makoto, Suzuki, Eiji, Kondo, Yuya, Matsumoto, Isao, et al; Overexpression of Tristetraprolin Regulates Collagen Induced Arthritis [abstract]. Arthritis Rheum 2009;60 Suppl 10 :661
DOI: 10.1002/art.25741

Abstract Supplement

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