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Partial construction of apoptotic pathway in PBMC obtained from active SLE patients and the significance of plasma TNF-α on this pathway

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Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder that affects various organs and systems. Increased apoptosis, together with defects in the uptake of apoptotic bodies, are thought to have a pathogenic role in SLE. By detection of chromatin condensation, 30% of apoptosis was detected in peripheral blood mononuclear cells (PBMC) from Thai patients with active SLE. Therefore, understanding of the molecular processes in PBMC apoptosis may allow us to gain insight into pathophysiology of SLE. Thus, genes involved in the apoptosis of PBMC from these patients were investigated ex vivo by cDNA array analysis. Seventeen apoptosis-related genes were stimulated in active SLE, more than twofold higher than in inactive SLE. These genes are classified into six groups, namely death receptors, death ligands, caspases, bcl-family, and neutral proteases and genes involved in endoplasmic reticulum stress-mediated apoptosis, such as caspase-4 and GADD153. Among those stimulated genes, tumor necrosis factor (TNF) and the TNF-receptor family were drastically up-regulated 60- and 19-fold higher than in healthy controls, respectively. Moreover, the degree of apoptosis correlated with the level of TNF-α in plasma, suggesting that the TNF family plays a role in the induction of apoptosis in SLE. To verify this hypothesis, PBMC from healthy individuals were treated with plasma from active SLE patients in the presence or absence of etanercept, a TNF inhibitor. In the presence of etanercept, active SLE plasma reduced the level of apoptosis to 26.43%. In conclusion, massive apoptotic death of PBMC occurred during the active stage of SLE. The molecular pathway of SLE-PBMC apoptosis was mediated at least via TNF/TNFR signaling pathway, which was confirmed by functional test of TNF-α in SLE patients’ plasma.

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Acknowledgements

We gratefully thank all the patients and all the medical staffs who generously collaborated with this research. We are grateful to Ms. Oravan Verasertniyom and the staff of the Division of Allergy Immunology and Rheumatology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University for providing us the samples. We also thank Prof. Jisnuson Svasti for critical editing of the manuscript. This work is supported by Mahidol University Research Grant (Grant number 02011854-0005) to Yindee Kitiyanant.

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Authors and Affiliations

  1. Department of Microbiology, Faculty of Science, Mahidol University, 272 Rama VI Rd., Rachtevee, Bangkok, 10400, Thailand

    Dhanesh Pitidhammabhorn & Sukathida Ubol

  2. Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 RamaVI Rd., Rachtevee, Bangkok, 10400, Thailand

    Surasak Kantachuvesiri & Kitti Totemchokchyakarn

  3. Department of Anatomy, Faculty of Science, Mahidol University, 272 Rama VI Rd., Rachtevee, Bangkok, 10400, Thailand

    Yindee Kitiyanant

  4. Institute of Science and Technology for Research and Development, Mahidol University, Salaya, Nakornpathom, 73170, Thailand

    Yindee Kitiyanant

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  1. Dhanesh Pitidhammabhorn
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  2. Surasak Kantachuvesiri
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  3. Kitti Totemchokchyakarn
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  4. Yindee Kitiyanant
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  5. Sukathida Ubol
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Correspondence to Sukathida Ubol.

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Pitidhammabhorn, D., Kantachuvesiri, S., Totemchokchyakarn, K. et al. Partial construction of apoptotic pathway in PBMC obtained from active SLE patients and the significance of plasma TNF-α on this pathway. Clin Rheumatol 25, 705–714 (2006). https://doi.org/10.1007/s10067-005-0162-5

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  • DOI: https://doi.org/10.1007/s10067-005-0162-5

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