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
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.
(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.
(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.
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