, Volume 12, Issue 3, pp 475–487 | Cite as

The functional haplotype of peptidylarginine deiminase IV (S55G, A82V and A112G) associated with susceptibility to rheumatoid arthritis dominates apoptosis of acute T leukemia Jurkat cells

  • Hui-Chih Hung
  • Chien-Yu Lin
  • Ya-Fan Liao
  • Pei-Chen Hsu
  • Gregory J. Tsay
  • Guang-Yaw Liu


Peptidylarginine deiminase IV (PADI4) posttranslationally converts peptidylarginine to citrulline. It plays an essential role in immune cell differentiation and apoptosis. A haplotype of single-nucleotide polymorphisms (SNPs) in PADI4 is functionally relevant as a rheumatoid arthritis (RA) gene. It could increase enzyme activity leading to raised levels of citrullinated protein and stimulating autoantibody. Previously, our study showed that inducible PADI4 causes haematopoietic cell death. Herein, we further investigate whether RA risk PADI4 haplotype (SNP PADI4; S55G, A82V and A112G) and the increase of its enzymatic activity induce apoptosis. In the tetracycline (Tet)-On Jurkat T cells, ionomycin (Ion) only treatment didn't induce apoptosis however it promoted inducible PADI4-decreased cell viability and -enhanced apoptosis. Through in vitro and in vivo PADI enzyme activity assay, we demonstrated that PADI4 enzyme activity of SNP PADI4 was higher than RA non-risk PADI4 haplotype (WT PADI4). The effect of SNP PADI4-induced apoptosis was superior to WT PADI4. In addition, both Ion and SNP PADI4 synergistically provoked apoptosis were compared with both Ion and WT PADI4. Concurrently, in the conditionally inducible SNP PADI4 cells of Ion treatment-induced apoptosis, not only the expression of Bcl-xL was down-regulated and Bax up-regulated, but also cytochrome c was released from mitochondria to cytoplasm in significant amounts. Western blotting data showed the increase in apoptosomal caspase activation during programmed cell death in the inducible SNP PADI4 cells subsequent to Ion treatment. These data demonstrated that both SNP PADI4 increasing their enzyme activity could enhance apoptosis through the mitochondrial pathway and further provide a conceivable explanation in the pathogenesis of RA following the upregulation of PADI4 activity in its SNPs.


PADIs SNP PADI4 Apoptosis Bax Bcl-xL Cytochrome c 



Peptidylarginine deiminases


Single nucleotide polymorphism





This study was financially supported by the Chung Shan Medical University grant CSMU 94-OM-A-098, 95-OM-A-103, 95-OM-A-104, and by grants from the National Science Council NSC 93-2745-B-040-005-URD, 94-2745-B-040-008-URD and 95-2745-B-040-009-URD.


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of Life SciencesNational Chung-Hsing UniversityTaichungTaiwan, ROC
  2. 2.Institute of ImmunologyChung-Shan Medical UniversityTaichungTaiwan, ROC
  3. 3.Department of MedicineDa-Chien General HospitalMiao-LiTaiwan, ROC
  4. 4.Department of Internal Medicine, Chung-Shan Medical University Hospital and Institute of ImmunologyChung-Shan Medical UniversityTaichungTaiwan, ROC

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