New disease-modifying antirheumatic drug 2 acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (KE-298) selectively augments activation-induced T cell death.

Abstract

We examined in this study whether the newly developed disease-modifying antirheumatic drug (DMARD) 2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (KE-298) augments activation-induced T cell death. Peripheral blood (PB) T cells, isolated from healthy donors, were activated by incubation with interleukin-2 (IL-2) followed by further culture with 12-0-tetradecanoyl phorbol 13-acetate (PMA) and ionomycin in the presence or absence of KE-298. The apoptosis of activated T cells was examined by flow cytometric determination of hypodiploid DNA. Fas expression and caspase-3 activity in activated T cells were also examined by flow cytometry, and expression of Fas ligand (FasL), Bcl-2-related proteins, and X chromosome-linked inhibitor of apoptosis protein (XIAP) was determined by Western blot analysis. Apoptosis was not obvious in resting T cells and was not augmented by KE-298. In contrast, apoptosis was clearly detected in activated T cells (activation-induced T cell death) with the increment of caspase-3 activity, and incubation of these cells with KE-298 further enhanced apoptosis. Treatment of activated T cells with KE-298 increased Bax expression but decreased XIAP expression without affecting the expression of Fas/FasL. Thus caspase-3 activity in activated T cells appeared to be increased by KE-298. Our results suggest that the newly developed DMARD, KE-298, selectively augmented activation-induced T cell death. This finding may contribute to the therapeutic efficacy of KE-298 in rheumatoid arthritis (RA) patients and provide new insight into the pharmacologic action of DMARDs.

• Authors: S Urayama, A Kawakami, T Nakashima, S Yamasaki, A Hida, H Ida, M Kamachi, H Nakamura, T Origuchi, K Migita, Y Kawabe, K Eguchi
• Journal: The Journal of laboratory and clinical medicine (J Lab Clin Med) Vol. 138 Issue 1 Pg. 11-7 (Jul 2001) ISSN: 0022-2143 [Print] United States
• PMID: 11433223 (Publication Type: Journal Article)

Chemical References

• Antirheumatic Agents
• BCL2L1 protein, human
• Cysteine Proteinase Inhibitors
• FASLG protein, human
• Fas Ligand Protein
• Membrane Glycoproteins
• Oligopeptides
• Phenylpropionates
• Proteins
• Proto-Oncogene Proteins c-bcl-2
• X-Linked Inhibitor of Apoptosis Protein
• XIAP protein, human
• aspartyl-glutamyl-valyl-aspartal
• bcl-X Protein
• fas Receptor
• CASP3 protein, human
• Caspase 3
• Caspases
• esonarimod

Topics

• Antirheumatic Agents (pharmacology)
• Apoptosis (drug effects, immunology)
• Blotting, Western
• Caspase 3
• Caspases (metabolism)
• Cells, Cultured
• Cysteine Proteinase Inhibitors (pharmacology)
• Fas Ligand Protein
• Flow Cytometry
• Humans
• Lymphocyte Activation (drug effects, immunology)
• Membrane Glycoproteins (analysis, metabolism)
• Oligopeptides (pharmacology)
• Phenylpropionates (pharmacology)
• Proteins (analysis, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (analysis, metabolism)
• T-Lymphocytes (chemistry, cytology, enzymology)
• X-Linked Inhibitor of Apoptosis Protein
• bcl-X Protein
• fas Receptor (analysis, metabolism)