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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

Apoptosis volume 12, pages 475–487 (2007)Cite this article

Abstract

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.

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Abbreviations

PADIs:

Peptidylarginine deiminases

SNP:

Single nucleotide polymorphism

Ion :

Ionomycin

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Acknowledgments

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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Affiliations

  1. Department of Life Sciences, National Chung-Hsing University, No. 250, Kuo-Kuang Road, Taichung, Taiwan, ROC

    Hui-Chih Hung, Ya-Fan Liao & Pei-Chen Hsu

  2. Institute of Immunology, Chung-Shan Medical University, No. 110, Sec. 1, Chien-Kuo N. Road, Taichung, Taiwan, ROC

    Chien-Yu Lin & Guang-Yaw Liu

  3. Department of Medicine, Da-Chien General Hospital, Miao-Li, Taiwan, ROC

    Pei-Chen Hsu

  4. Department of Internal Medicine, Chung-Shan Medical University Hospital and Institute of Immunology, Chung-Shan Medical University, Taichung, Taiwan, ROC

    Gregory J. Tsay

Authors
  1. Hui-Chih Hung
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  2. Chien-Yu Lin
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  3. Ya-Fan Liao
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  4. Pei-Chen Hsu
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  5. Gregory J. Tsay
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  6. Guang-Yaw Liu
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Corresponding authors

Correspondence to Hui-Chih Hung or Guang-Yaw Liu.

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The authors (H.-C. Hung and C.-Y. Lin) contributed equally to this paper.

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Hung, HC., Lin, CY., Liao, YF. et al. 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. Apoptosis 12, 475–487 (2007). https://doi.org/10.1007/s10495-006-0005-0

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Keywords

  • PADIs
  • SNP PADI4
  • Apoptosis
  • Bax
  • Bcl-xL
  • Cytochrome c